STAKEHOLDER OPINIONS ON THE POSITION OF THE … · DCTF Dutch Clinical Trial Foundation EC Ethics...

STAKEHOLDER OPINIONS ON THE POSITION OF THE

NETHERLANDS IN CONDUCTING CLINICAL DRUG TRIALS

A SWOT ANALYSIS

25 January 2011

Author:

Myrthe P. Rijswijk-Trompert, LL.M. Salvius Legal B.V.

Editorial support:

Hiddo Lambers Heerspink, PhD Department of Clinical Pharmacology University Medical Centre Groningen

Floris Buijzen, MSc Dutch Clinical Trial Foundation

Advisory Board:

Dr. HJ Lambers Heerspink Department of Clinical Pharmacology, University Medical Centre Groningen, Groningen

Ms. T Hoffman Quintiles, Hoofddorp

Prof. dr. NS Klazinga Academic Medical Centre Amsterdam, Dutch Clinical Trial Foundation

Ms. dr. I Klingmann Project Coordinator ICREL

Ms. ir. N Kraaijeveld Nefarma, Den Haag

Prof. dr. HGM Leufkens Division of Pharmacoepidemiology and Pharmacotherapy, Utrecht University,

Medicine Evaluation Board, The Hague

Prof. dr. HJ Out Women's Health Global Clinical Research, MSD, Oss

Prof. dr. RJW Tijssen Centre for Science and Technology Studies (CWTS), Leiden University, Leiden

Ms. dr. LE Visser Hospital Pharmacy, Erasmus Medical Centre Rotterdam

Prof. dr. D de Zeeuw Department of Clinical Pharmacology, University Medical Centre Groningen, Groningen

Table of contents

List of relevant acronyms ............................................................................................................................. …………4

Introduction .................................................................................................................................................................... 6

SECTION I - ANALYSIS ................................................................................................................................................. 8

1 Opinions per topic of different stakeholders ............................................................................................ 9

1.1 CA and METC approval process .............................................................................................................. 9

1.2 Effects implementation EU CTD ........................................................................................................... 10

1.3 Standardization of clinical trial documents ..................................................................................... 11

1.4 Data protection ........................................................................................................................................... 12

1.5 The quality of clinical research in the Netherlands ...................................................................... 12

1.6 Costs ................................................................................................................................................................ 13

1.7 Recruitment and motivation of investigators ................................................................................. 13

1.8 Training and education investigators ................................................................................................ 14

1.9 Infrastructure hospitals ........................................................................................................................... 15

1.10 Recruitment of study subjects ............................................................................................................... 16

1.11 Collaboration industry, CROs and academic hospitals ................................................................ 17

1.12 Access to well-trained CRO staff ........................................................................................................... 17

1.13 The value of Dutch organizations ........................................................................................................ 18

1.14 Trends in clinical research ..................................................................................................................... 19

1.15 The effects of globalization ..................................................................................................................... 20

1.16 The role of the Dutch government ....................................................................................................... 20

1.17 Is the Netherlands an attractive country to establish your company .................................... 22

2 SWOT analysis .................................................................................................................................................... 24

2.1 Strengths ........................................................................................................................................................ 24

2.2 Weaknesses .................................................................................................................................................. 25

2.3 Opportunities ............................................................................................................................................... 26

2.4 Threats ........................................................................................................................................................... 27

3 Recommendations ............................................................................................................................................. 29

SECTION 2: INTERVIEWS ........................................................................................................................................ 34

T. van Gelder, MD (Erasmus MC, Rotterdam) .............................................................................................. 35

P.A.B.M. Smits, MD FFPM (Radboud University Nijmegen Medical Centre).................................... 41

F.H. Bosch, MD (Rijnstate Hospital/Alysis Zorggroep) ............................................................................ 47

O.B. Jochems, MD (MediServ) ............................................................................................................................ 53

A.F. Cohen, MD PhD FFPM (CHDR) .................................................................................................................. 59

A. Huisman, MSc (PRA International) ............................................................................................................. 65

Ms. L. Becker (Quintiles) ...................................................................................................................................... 70

H.J. Out, MD PhD (MSD) ........................................................................................................................................ 76

A. Keijzer, MSc and A.G.M. van de Langerijt, MSc (Sanofi-aventis) .................................................... 83

J. Rijnierse, MD (Amgen) ..................................................................................................................................... 91

List of relevant acronyms

ACRON Association of Clinical Research Organisations in the Netherlands

AMC Academic Medical Centre

BROK Basiscursus Regelgeving en Organisatie voor Klinisch onderzoekers

CCMO Centrale Commissie Mensgebonden Onderzoek

CEO Chief Executive Officer

CRA Clinical Research Associate

CRCN Clinical Research Centre Nijmegen

CRO

CA

Contract Research Organisation

Competent Authority

CTA Clinical Trial Agreement

CTMM Centre for Translational Molecular Medicine

DCTF Dutch Clinical Trial Foundation

EC Ethics Committee

EFGCP European Forum for Good Clinical Practice

EMA European Medicines Agency

ESF European Science Foundation

EU CTD European Union Clinical Trials Directive

EZ Ministerie van Economische Zaken (Economic Affairs)

FDA Food and Drug Administration

GCP Good Clinical Practice

GLP Good Laboratory Practice

GMP Good Manufacturing Practice

GP General Practitioner

ICH-GCP International Conference on Harmonisation – Good Clinical Practice

IND Investigational New Drug

KOL Key Opinion Leader

LATAM Latin America

LSH

LUT

Life Sciences&Health

Lokale Uitvoerbaarheidstoetsing

MC Medical Centre

MCRN Medicines for Children Research Network

MD Medical Doctor

METC Medisch Ethische Toetsings Commissie

MSD Merck, Sharp & Dohme

NHS National Health Services

NVMETC Nederlandse Vereniging van METCs (Dutch Association of METCs)

NVZ Nederlandse Vereniging van Ziekenhuizen (Dutch Association of Hospitals)

PI Principal Investigator

PR Public Relations

PSN Pharmaceutical Services Network

R&D Research & Development

SMO Site Management Organisation

SOP Standard Operating Procedure

STZ Samenwerkende Topklinische Ziekenhuizen (Cooperating topclinical

hospitals)

SWOT Strength, Weaknesses, Opportunities and Threats

TIPharma Top Institute Pharma

UMC University Medical Centre

VWS Ministerie van Volksgezondheid, Welzijn en Sport (Public Health, Welfare

and Sport)

Introduction

Traditionally, the Netherlands has been at the forefront of clinical drug research. This can be

attributed to: the high level of education received by the investigators, the large number of key

opinion leaders, the high standard of care, the excellent networks available for patient

recruitment, the specialist centres in place and the high quality and reliability of data

collection and reporting. Within a changing global clinical drug research environment with an

increasing number of competitive countries, it is therefore essential to have insight into the

strengths and weaknesses of the Netherlands as a clinical drug research country.

As part of this assessment, ten stakeholders participating in the Dutch clinical trial

environment were interviewed on this matter through a prepared list of questions. The

questions were presented in an open and general way, in order to provide the stakeholders

with the opportunity to present their own priorities with respect to the assessment. The

assessment was completed with specified questions to get some more in-depth information on

the most relevant topics. The interviews took place at the respective stakeholders’ location in

August and September of 2010. The group of participants consisted of: three Medical Directors

of pharmaceuticals companies, two representatives of a Phase I unit, two representatives of a

CRO, two principal investigators from an academic hospital and one principal investigator

from an STZ hospital.

Detailed minutes from each interview are presented in Section II of this report. These minutes

are segmented into different relevant topics in order to make a comparison between the

opinions of the different stakeholders. Section I presents the overall summary of the different

views of the position of the Netherlands and is completed with individual interpretations and

ideas.

The interviews have been used to construct a Strengths, Weaknesses, Opportunities and

Threats (SWOT) analysis. This analysis provides recommendations on how to maintain and

improve the competitive position of the Netherlands in the changing clinical research

environment.

SECTION I - ANALYSIS

Section 1: Analysis

9

1 Opinions per topic of different stakeholders

As stated in the general introduction, ten stakeholders from different areas of expertise in the

clinical research environment were interviewed to assess the strengths and weaknesses of

performing clinical research in the Netherlands. An extensive elaboration of the interviews can

be found in Section II of this report, segmented into various relevant topics. The current

section begins with an overall summary of the most important outcomes of the interviews per

topic. This summary is based on the perceptions and experience of the interviewees based on

the highest common factor and where interesting and important, completed with individual

interpretations and ideas. Based on the interviews, an overall SWOT analysis was constructed

on the position of the Netherlands in the field of clinical research. The SWOT section finishes

with a set of recommendations, based on the stakeholders’ opinions, on how to maintain and

improve the competitive position of the Netherlands in the changing clinical research

environment.

1.1 CA and METC approval process

CA approval process

All participating interviewees agreed that the Dutch Competent Authority (CA) approval

process in the Netherlands is excellent and superior to other European countries and also the

rest of the world. The process involves only a marginal assessment being made and if no

objections are posed by the CA within 14 days of submission, the clinical trial is approved.

METC approval process for Phase II-IV studies

Although the METC approval process is improving in the Netherlands, it is still considered a

negative aspect of the Dutch clinical trial environment by industry (CROs, biotech and

pharmaceutical companies). CRO’s observe that sponsors are beginning to ignore the

Netherlands when selecting countries for a clinical trial. Furthermore, pharmaceutical and

biotech companies observe that it is becoming increasingly more difficult to convince their

head office to consider selecting the Netherlands as a country for their clinical trial. The main

reason is that patient recruitment compared to other European countries (e.g. Belgium) starts

too late due to the slow METC approval process. To secure the first patient in such a study is

not the major concern. The main problem is that due to the long duration of the approval

process, it takes too long before all sites are up and running for a trial with competitive

recruitment. In many cases, the Dutch sites often do not get the chance to substantially

contribute.

This delay is mainly due to local feasibility committees simply not accepting the central METC

approval and instead making their own assessment of the submission documents (e.g. they are

Section 1: Analysis

10

commenting on the protocol, instead of only looking at the local feasibility and the patient

information). There is however a tendency visible within METCs and local feasibility

committees to try and create a more efficient procedure in order to deal with the workload and

be competitive (e.g. by creating smaller committees or subcommittees).

A further reason for delay is that that the preparation and collection of the required

submission package is taking too much time. It has shown to be effective when industry (the

initiators of a clinical drug trial) assists the investigators with this task which subsequently

speed up the process.

METC approval process for Phase I studies

The METC approval process for Phase I studies in the Netherlands is very favourable. It usually

takes about two weeks from submission to approval, which is fast compared to other countries

such as Germany where it takes 60 days or France where it takes 21 days. In the US it can take

up to 3 months to open an IND for a Phase I trial. The Netherlands is in this respect, very

competitive on a global scale.

General comments

On a global scale and with respect to the type of study where a sponsor needs to include large

amounts of naïve patients, the METC approval process being used as a delaying factor is

apparently not the most critical one, since in China and Brazil the approval process takes

substantially longer and still these countries are very popular countries with the industry in

this respect. However, at a European level the Netherlands is actually surrendering their

competitive position to other countries in Europe, like Belgium, which is still a country that is

considered by industry on a more regular basis. Principal investigators commented that it

would also be interesting to not only look at the METC approval process, but also at timelines

(e.g. the time between METC approval and the first patient in the study) and in that regard

identify whether there are other delaying factors in the process that should be taken into

account.

1.2 Effects implementation EU CTD

Increase of bureaucracy

All participants agreed that, with the implementation of the EU CTD, performing a clinical trial

in the Netherlands has become overly bureaucratic, due to the additional administrative and

reporting requirements. However, this is no different from other European countries and as

such does not have an impact on the competitive position of the Netherlands.

Section 1: Analysis

11

Stricter interpretation

Another aspect that does affect our competitive position is that in certain ways the EU CTD is

interpreted in a stricter way in the Netherlands than in other European countries. This is

particularly the case with regard to the approval requirements for paediatric trials, trials with

orphan diseases and gene therapy trials. It represents a missed opportunity, since the

Netherlands has an excellent network for paediatric trials (MCRN) in place and is specifically

well equipped for more complex gene therapy trials.

Further harmonization METC approval process

A threat to the Phase I clinical trial environment would be the further harmonization of the

METC approval process with arrangement of the process at a European level. This would result

in the levelling of approval timelines and would jeopardize our competitive position. Such

harmonization of the approval process would in general create further delays. It is unlikely that

METCs (which are gradually beginning to accept the assessments of their Dutch colleagues)

would have no problems accepting an approval provided by an METC in Hungary for example.

1.3 Standardization of clinical trial documents

Need for standardization

Principal investigators and the industry at large have indicated that the clinical trial process

(and specifically the approval process) would be faster and more efficient if documents, such as

the patient informed consent form and the clinical trial agreements are standardized for

clinical drug research in the Netherlands.

Patient information

The patient information form is now a document that is often checked and if deemed necessary

adjusted by all participating local feasibility committees separately.

Site agreements

Contract negotiations also tend to be slow, usually because hospital lawyers are not aware of

the time sensitivity of clinical research. In principle, this is not typical for the Netherlands,

since it is a tendency which is reflected on a global scale. However, now that the CCMO has

established guidelines which require a signed clinical trial agreement at the METC submission,

this creates an additional hindering factor for the Netherlands.

Initiatives

The CCMO and Nefarma are taking initiatives to standardize the patient information form and

site agreements. The CCMO has posted a patient information form template on their website.

Nefarma is currently finalizing a site contract template that is based on the template proposed

Section 1: Analysis

12

by the CCMO. Nefarma members have agreed upon this template (pharmaceutical and biotech

companies with a subsidiary in the Netherlands) and Nefarma is now consulting with other

parties in order to garner their input. Nefarma acknowledges that a standardized site

agreement can only work if: there is a solid basis and support from the local pharmaceutical

and biotech industry, the CRO industry and the academic and STZ hospitals, such an approach

would be similar to the situation with the NHS Trust template in the UK. In the case of the UK,

the NHS Trust recognizes that (local subsidiaries of) the different parties have already

previously approved the template and that it is not necessary to make substantial changes to

the standard template. If such a change is not implemented it is likely that US based sponsors

will continue to insist on using their own templates.

1.4 Data protection

At an international level, companies located in the EU are starting to implement procedures

and structures aimed at ensuring compliance with the Data Protection Directive. However, at a

local level this topic does not seem to be at the top of the agenda in the Dutch clinical research

environment. Of course, parties do take into consideration the data privacy requirements with

respect to the patient data. But, in the Netherlands not as much attention is paid to the topic of

patient information and informed consent, as for instance is paid in Germany.

1.5 The quality of clinical research in the Netherlands

Availability of quality, expertise and Key Opinion Leaders

The Netherlands is still a very appealing country for clinical trial sponsors; it has a reputation

for its scientifically high quality investigators and research staff, has a wide availability of key

opinion leaders, possess technical and scientific expertise and also the high quality and

reliability of the data.

Scientific output and input

The Netherlands is a small country with a relatively high output: investigators are submitting

many high-level publications and are well represented at important conferences. When a

sponsor needs technical and scientific input on its protocol, the Netherlands is an appealing

country due to the availability of expertise on the studies of a more complex nature.

Infrastructure

The infrastructure in place for performing clinical trials in the Netherlands is also very good:

excellent specialist centres, good universities, a large number of useful collaborations between

different organizations, useful networks and a good health care system.

Section 1: Analysis

13

In addition, communication between the pre-clinical and clinical phase in the Netherlands is

outstanding.

Mentality

In general, Dutch investigators are known for their down to earth mentality and for taking the

integrity of the study data very seriously. They are also willing to collaborate at an

international level.

1.6 Costs

Phase II-IV trials

For Phase II-IV studies, the cost of performing a clinical trial in the Netherlands is widely

comparable to similar Western-European countries such as Germany. It is more expensive than

Southern-European countries, but less expensive than the UK and Nordic countries. Compared

to the US, scientifically educated staff are less expensive to recruit. Lastly, compared to

countries in the emerging markets (Asia, LATAM), Western-European countries, including the

Netherlands, are much more expensive.

Phase I trials

Performing a Phase I trial in the Netherlands is relatively expensive (more expensive than

other European countries). Because of the high level of technical and scientific expertise and

the fast start-up timelines, sponsors are still willing to pay.

1.7 Recruitment and motivation of investigators

Motivation of Dutch investigators

In general, Dutch investigators are enthusiastic about participation in clinical trials, since they

acknowledge that clinical trials contribute to improved healthcare. It is however, difficult to

motivate an investigator who has responsibility for direct patient health care to participate in a

clinical trial and has to perform a clinical trial “on the side” without any support from the

hospital. Money is usually not a decisive factor in such case, as it does not remove the obstacles.

Moreover, with increased regulations funding is usually required to compensate additional

resources, such as research nurses, in order to deal with the administration inherent in

contemporary clinical trials.

Sponsor initiated trials

Dutch investigators are in general, better equipped and more motivated for studies that

require some technical and scientific input. Industry sponsored confirmatory trials are

therefore usually considered less interesting by investigators because there is often little

Section 1: Analysis

14

opportunity to provide such input and seldom the possibility to publish. Some hospital

departments do see the benefit of participating in this type of trial and are prepared to provide

the remuneration for more interesting research. Some investigators have also tried to

negotiate one or more sub-studies that are scientifically more interesting. For proof-of-concept

studies, new compound trials or trials focusing on an interesting indication it proves

complicated to recruit and motivate investigators. Specialists do not show enough interest in

Phase IIa trials. If this does not change, there is the distinct possibility that this type of research

will disappear in the Netherlands.

Key Opinion Leaders

For Key Opinion Leaders (KOLs) it tends to be easier to negotiate more interesting terms with

a sponsor. It appears that KOLs are regularly not involved at the operational level of a clinical

trial. The involvement of KOLs in the daily operation of clinical trials together with other

investigators is considered to be important by various parties to stimulate the conduct of

clinical trials.

Studies with General Practitioners

In general, Dutch general practitioners (GPs) have limited experience in conducting clinical

trials.. The most likely explanation lies in the fact that the administrative burden in the regular

GP practice is high so that limited time is left for the conduct of clinical trials. In addition, the

logistics (e.g. ensuring that all GPs are trained on ICH-GCP) and the fragmented nature of

patient recruitment are not ideal. Parties that wish to perform a GP trial can partially overcome

these obstacles by providing support in the daily operations of the trial and by investing in a

strong relationship with the GP. Initiatives to improve the conduct of clinical trials at the GP

offices are currently ongoing. Some GP co-operations have made an effort to set up a solid

infrastructure for clinical research, which is highly appreciated and supported by the

pharmaceutical, biotech and CRO industries.

1.8 Training and education investigators

Education

Generally, the education of the investigators and study staff is internationally perceived to be

of high quality. In order to create a setting in which more top clinical research is carried out, all

players in the clinical research environment should take responsibility for the training and

education of investigators and staff who have to deal with high quality clinical trials. Some

parties are already providing interesting education and training opportunities related to

clinical research (CHDR, Erasmus MC). Nevertheless, there is insufficient collaboration and

vision on an integrated country-wide approach with respect to education of the required

investigators and clinical research staff.

Section 1: Analysis

15

ICH-GCP

Investigators in the Netherlands are not always fully aware of the ICH-GCP requirements. Some

investigators have a perception of the training regulations as very demanding in comparison to

other types of research. The probiotics trial has exposed the reality that the Dutch clinical

research environment still needs improvement with respect to ICH-GCP compliance. The

possibility of providing ICH-GCP training to investigators could be fulfilled in the investigator

meeting. Unfortunately, in practice the investigators tend to send their research nurses

believing them to have enough experience to perform the research.

An effective initiative is the BROK-course (which was originally set up to educate academic

researchers on the ICH-GCP guidelines) but is now also very popular for investigators in other

hospitals. Improving research quality through better training can be used to strengthen our

competitive position. The down-side at this stage is that the demand for education is bigger

than the supply. A positive development here is the decision by some relevant Master course

providers to make ICH-GCP part of the curriculum (e.g. Health Science at the VU).

Registration and certification

Different pharmaceutical and biotech companies do not always accept each other’s ICH-GCP

certificates. Their policy is often that the participating investigators need ICH-GCP training and

a certificate from the relevant company or from an accredited training institute.

The difficulty in the Netherlands is that at the moment there is no system for assigning

accredited training institutes and there is no central registration of ICH-GCP trained

investigators. Only participants of the BROK-course are centrally registered with certificates

accepted as originating from an accredited training institute. It would significantly improve

conditions if the Dutch authorities would assign accredited training institutes and arrange for

the central registration of trained investigators. The ICH-GCP training could be less extensive

and time consuming than the BROK-course through provision of training in the form of e-

learning, which, because of its efficiency also makes it easier to reach the principal

investigators.

1.9 Infrastructure hospitals

Support hospital

Clinical research is usually not supported by the relevant hospital. This is particularly evident

with regard to industry sponsored research: it is not considered particularly prestigious and

the opinion prevails that this type of research costs the hospital money and that the

investigators are the only party benefiting. In Radboud University Nijmegen Medical Centre, a

hospital gratuity system is in place based on the performance of the investigators. This system

Section 1: Analysis

16

aims to create possibilities for the most successful investigators to dedicate more time to

research.

Research Desks

A positive trend is the establishment of (clinical) research desks in hospitals. Nonetheless, each

department currently can only have its one desk and the main focus remains on the contractual

part, with less focus on collaboration with the laboratory and pharmacy. However, if these

desks are set-up as a multidisciplinary platform for research, administration and organization,

the clinical research process in hospitals becomes more efficient and it could provide a better

facilitation for sponsors and CROs that perform clinical trials in the Netherlands.

Parties believe it would be preferential to set-up the research desks in such a way that these

facilities are available for the departments, whilst at the same time they are not obliged to

conduct the trial with the help of the research desk. Making use of the clinical research desk

compulsory would only add another level of bureaucracy to the process. Additionally,

successful investigators and their department will be discouraged from involvement if they

have to share their achievement with the less successful departments.

Investments CRO and pharmaceutical industry

CRO and pharmaceutical industry are making efforts to improve collaboration with hospitals

and hospital boards to overcome the collaboration bottlenecks (e.g. Quintiles’ prime site and

partner sites initiative and sanofi-aventis’ Research Proof).

1.10 Recruitment of study subjects

Small patient pool

For therapeutic confirmatory trials, industry is nowadays looking at actual patient recruitment

rates. The Netherlands, being a small country with a relatively small patient population, is not

very competitive in this respect. CCMO data shows that approximately 100.000 patients per

year are recruited for clinical trials, which is a relatively high number of patients for such a

small country.

Reason participation

The most important reason behind a patients’ decision to participate in a trial is their trust in

the opinion of their treating physician. Other relevant factors that influence a patients’ decision

are the perceived image of the pharmaceutical industry and clinical research in general, and a

lack of awareness of the benefits that can be gained from participating and in the subsequent

improvement of healthcare. Nefarma is making an effort to remedy this situation.

Section 1: Analysis

17

Improve recruitment

Pharmaceutical companies and CROs are investing in the support and motivation of the

investigational sites. They also emphasize the importance of a thorough feasibility assessment

before opening a site. In hospitals it is important that everyone is aware of ongoing clinical

trials, in order not to miss any potential subjects that visit the hospital.

Networks

The Netherlands has a solid infrastructure and excellent networks for gynaecology, cardiology,

diabetes and hypertension at its disposal.

Healthy volunteers

The recruitment of healthy volunteers is not too problematic. The reimbursement is

considered attractive, and advertising has proven to be very effective.

1.11 Collaboration industry, CROs and academic hospitals

In the Netherlands there are many collaborations between industry, government and academic

hospitals. CTMM (Centre for Translational Molecular Medicine) and TIPharma (Top Institute

Pharma) are public-private partnerships between government, industry and universities.

These initiatives depend on input from local R&D, which now is only comprised of Organon

(MSD). Unfavourable Intellectual Property arrangements make it difficult for local

pharmaceutical offices to get approval for participation in these partnerships from the head

office. Hospitals are also collaborating successfully on clinical trials at a national and regional

level. These features can be further explored and manipulated in order to strengthen the

position of the Dutch clinical research environment. Potential collaborations at a European

level could be investigated, but realistically the Netherlands would then have to compete with

other countries and different governments would interfere.

1.12 Access to well-trained CRO staff

Competitive market

The market for finding adequate, qualified and trained CRO staff is very competitive in the

Netherlands. High salaries, good secondary labour conditions and fierce competition make it

challenging. In addition it is not a prestigious industry to work in, which makes the pool of

available staff considerably smaller. Where it used to be possible to hire several CRAs from a

small local CRO, this is now much harder due to the large number of mergers and acquisitions

in the CRO industry. In this way, the once small and local CRO has become a direct competitor.

Section 1: Analysis

18

The Netherlands as CRO country

Local pharmaceutical and biotech companies are not directly involved with respect to the

availability of qualified local CRO staff for Phase II-IV studies. Decisions on contracting a CRO

for these clinical trials are made at an international level and the CROs that are contracted are

global organizations. It is therefore not worthwhile seeking possibilities to market the

Netherlands as a good CRO country. Only in countries where the clinical research

infrastructure and level of quality are not yet well developed is the choice of a local CRO

critical.

1.13 The value of Dutch organizations

Value

All parties agree that the existence of organizations that are dedicated to the improvement of

the local clinical trial climate, such as Nefarma, ACRON and DCTF, are very valuable. A

successful initiative by the DCTF was to bring the hospital boards and industry players

together in order to create a better awareness and understanding between parties. This in turn

facilitates their collaboration and also improves the clinical research process. Life Sciences and

Health is an organization that has built some useful bridges, but has not included the CRO

industry thus far. In general, the opinion is that organizations are starting to make a positive

difference to the clinical research environment in the Netherlands, but still have to increase

their efforts in order to improve the Dutch competitive position in Europe and the rest of the

world.

Influence

Nefarma has put great effort into establishing a good connection with the government and the

CCMO. The ACRON and DCTF should aim to achieve a stronger say at a more structural level

with the interested parties, including: government, the CCMO and the other authorities that

decide upon the clinical research process and environment. Due to the importance of

preventing further harmonization of the approval process and in doing so maintaining the

Dutch competitive position for Phase I trials in the world, it is paramount that the ACRON and

DCTF are able to convince the CCMO to take a stand on this topic. The impression is however

that the CCMO does not acknowledge the ACRON and DCTF as valuable discussion partners yet.

Collaboration

The existing problems affecting the clinical research environment are often not approached in

an coordinated way by the different organizations involved. Instead of joining forces, they are

focusing on certain topics separately and in an isolated way.

Section 1: Analysis

19

1.14 Trends in clinical research

Shift to early phases

Several interviewed parties believe that, in the future the emphasis in clinical research will

shift more towards the early stage trials. Because of cost saving, the industry is concerned with

receiving more insurance on the potential failures and success of a product at an earlier stage.

Expectations are that human testing will also start at an earlier stage. The Netherlands is well-

equipped for the early stage research required for this type of testing (e.g. translational

medicine).

Indications and compounds

In the past cardiovascular trials were very popular, but gradually a shift towards oncology

trials became visible. The Netherlands enjoys a strong position in this respect, due to the large

number of Key Opinion Leaders and good infrastructure in place for this indication. Other

trends in clinical research are trials with small indications (development of specific innovative

drugs), ageing diseases and paediatric trials. In the Netherlands there exist excellent networks

for paediatric trials. A weakness exists here in that the regulations in the Netherlands

(regarding this type of trial) are stricter than in other European countries and that the network

has not yet able to mature. This makes pharmaceutical companies cautious when deciding in

which country to base a paediatric trial. Personalized medicine (medicines developed for

genetic subsets) and antibiotics research (because of the resistance that is developed for

existing antibiotics) are also trends that can be expected in clinical research.

International collaboration

In order to maintain a meaningful position in the international clinical trial environment, it is

important to focus on international collaboration. In the future, institutes may arise that focus

more on hospitals than on countries.

Insourcing

Current expectations are that the industry is increasing the insourcing of knowledge, especially

with regards to phase I research.

Publication of negative findings

The international development whereby negative and positive findings are both published is

fully supported by academic hospitals. The industry agrees with this principle, but fears that

the information is not always used for the right purpose.

Section 1: Analysis

20

1.15 The effects of globalization

Shift to the emerging economies

Now that pharmaceutical companies are looking at clinical research on a global scale, less

expensive alternatives to the Western countries trials are appearing which can deliver results

from a large amount of naïve patients. For therapeutic confirmatory trials (delivering patients

and collecting data) there is a clear shift visible towards these countries, and it is impossible

for the Netherlands to compete on this front. Furthermore, when industry links their

investments in clinical research to potential revenues the Netherlands is not a very appealing

country, due to the relatively small patient population.

The Netherlands is an interesting and exciting environment for more complex technical

research, because of its good infrastructure, expertise and knowledge. The investigators in the

emerging markets are very eager to learn and are developing at a fast pace, which in the long

term will affect the Dutch competitive position in this research stage as well. At this stage it

remains more expensive to manage clinical research in the more developing countries and

cultural differences continue to provide hurdles to overcome, but it is only a matter of time.

Further development will eventually bring these costs down to the level of Western countries.

Therefore it can be concluded that the biggest driving force behind the shift to the emerging

markets is and will be the recruitment of large numbers of naïve patients.

Acquisition of local R&D companies

To survive in a globalizing market, the industry has shown a trend in the past of companies

acquiring or merging with other companies. For the Netherlands this means that international

organizations are taking over local Dutch companies. Scientifically interesting research moves

away to the head office or other core locations of these organizations.

The risk is that high-quality investigators and talented scientists are moving away from the

Netherlands in order to work in locations where they can participate in scientifically

interesting research with high quality facilities. This would be an undesirable situation, since

the expertise and quality of our investigators are the pillars of Dutch clinical research. This

would also mean that whilst investments are being made in the education of scientists, the

Dutch clinical trial environment would not be able to benefit.

1.16 The role of the Dutch government

Organon (MSD)

Some of the interviewees were convinced that there was little the Dutch government could

have done to prevent the acquisition of Organon and the subsequent decision to (possibly)

close down the Dutch R&D unit. They are convinced that it is difficult to influence globalization

Section 1: Analysis

21

trends and the effect of market forces with which a multinational pharmaceutical organization

has to deal with.

Others interviewed indicated their belief that the government should have acted more pro-

actively instead of reactively in this situation, especially since MSD’s decision directly

influences the state of our knowledge economy and clinical research environment. The

government should have communicated with AKZO-NOBEL at a much earlier stage, made a

careful assessment of what the consequences of Organon’s acquisition would be and also

examined what possible options existed to influence that decision. Some also feel it would have

made a difference, if at the time, prime-minister Balkenende had contacted the CEO of MSD to

influence his decision (like Sarkozy supposedly has done) and fight for what is important for

the Netherlands knowledge economy, instead of letting the market forces have a free hand.

Image

Several Dutch politicians are not very supportive of the pharmaceutical industry in the media.

Instead of focusing on a few negative topics related to the industry it would be more

appropriate to give credit to the industry for their involvement in the improvement of health

care. Politicians should appeal to the people by stating that it is everyone’s responsibility to

support, collaborate and participate in the improvement process of our standard of care.

Collaboration VWS and EZ

The government should link economic activity to the clinical research and healthcare sectors in

our country, with Finland providing an example of how to do so. The government should pay

attention to investments made by pharmaceutical companies in the Netherlands and the

possibilities that the government has to collaborate, motivate and support the industry, all of

course within the boundaries of what is ethically justified. This would make the Netherlands a

more attractive, efficient and productive country and will be beneficial to the status of a

knowledge economy. To achieve this it is important for the departments of VWS and EZ to

improve their collaboration and define common goals.

Long term vision

In order to build and expand our knowledge economy, the government should show a

commitment to a long term vision and sustained continuity. TIPharma is for instance a very

good initiative, but the short reigning terms affecting the government prevent the initiative

growing and benefiting from previously offered investments. An alternative to this type of

initiative is to start up research with governmental funding and subsequently search for

external sponsoring in order to safeguard the continuity of the project.

Section 1: Analysis

22

Regulating responsibility

The government could support the clinical research environment by establishing clear and

strict rules on timelines for local feasibility assessments. In other ways, it would help the

clinical research environment if those regulations that account for unnecessary administrative

burdens or regulations that put the Netherlands in a less competitive position are revised.

These include the strict interpretation of the EU CTD with respect to gene therapy, orphan

diseases and paediatric trials. In order to improve the quality of clinical research in the

Netherlands, more governmental inspections could be carried out. However, this should not

only be based on following strict regulations, but in accordance with the rationale behind the

regulations.

1.17 Is the Netherlands an attractive country to establish your company

Company taxes

The Dutch tax regulations are very favourable and attractive for companies.

Rigid labour law

Labour law in the Netherlands is extremely rigid and in balanced favour of employees, which is

a disturbing concept for a foreign company to consider when deciding whether to house their

organization in the Netherlands. The fact that the decision concerning the reorganization of

Organon (MSD) was postponed due to the privileges of the enterprise committee under Dutch

labour law was not a good advertisement for the Netherlands as a country in which to establish

a local office.

Negative image pharmaceutical industry

The image of the pharmaceutical industry in the Netherlands is worse than anywhere else in

the world, due to the position of some politicians and academics that have access to the media.

There is not enough understanding, awareness and appreciation of the positive aspects of

sponsor initiated clinical research from which everybody benefits, such as improvement of our

standard of care.

Input government

If the government wishes to make the Netherlands a more attractive country for the biotech

and pharmaceutical industry it should link economic activities with scientific and healthcare

activities. In addition, it would make the Netherlands a more attractive country if the

government provided incentives to industry in order to stimulate clinical research in the

Netherlands (e.g. like the government in Switzerland).

Section 1: Analysis

23

Reimbursement and prescription of compounds

After the long and extremely expensive process of developing a new compound,

pharmaceutical and biotech companies have to overcome certain additional hurdles in order to

make the development of the compound worthwhile. Their compound has to be added to the

list of medicines that will be reimbursed by health care insurers otherwise their compound will

not be prescribed by physicians. Pharmaceutical and biotech companies struggle to get their

compounds on the reimbursement list in the Netherlands and in addition, Dutch GPs are very

reluctant to prescribe new compounds, which is blocking further innovation and is

discouraging for industry members.

Section 1: Analysis

24

2 SWOT analysis

2.1 Strengths

CA and METC approval process

The CA approval process in the Netherlands is faster and more efficient than in other

countries

Timelines of the METC approval process for Phase I trials in the Netherlands are short

compared to other countries, which is an important factor determining the current

competitive position of Dutch Phase I clinical research

Infrastructure

The Netherlands has an excellent Phase I setting

Infrastructure for phase IV trials is very good

Access to high quality investigators and research staff

Access to technical knowledge, experience and expertise

Excellent networks for gynaecology, cardiology, diabetes and hypertension

Very good knowledge and information infrastructure with data from population compared

to other countries in the world , and therefore very appealing for access and collection of

valuable research information (e.g. clinicalresearch.com, iGuard, Provenance)

Many collaborations between hospitals at a national and regional level

Valuable interactions between universities and industry

High standard of care

Training and education

High educational level of investigators and research staff

Quality

Availability of numerous important key opinion leaders

High publication output for a relatively small country

Good link between pre-clinical and clinical research

Good at early stage complex trials

Cultural tendency to collaborate internationally

Well-equipped to handle more technical studies

Image of reliable and incorruptible research environment

Business considerations

Favourable company tax regulations

Section 1: Analysis

25

2.2 Weaknesses


A slow METC approval process for phase II and III trials, which makes the Netherlands an

unattractive country for industry to select for their clinical trials, due to the eventual low

patient recruitment. The Dutch neighbour country Belgium is performing substantially

better in this respect.

Regulations

Unnecessary administrative burdens when performing a clinical trial

Lack of differentiation in regulations for different types of research

Infrastructure

Limited motivation for investigators to participate in generic trials (financially and

scientifically uninteresting)

Small patient population available and not many treatment-naïve patients available. This

makes the Netherlands not a very good “production country”.

Hospital boards have a very negative perception of sponsor initiated clinical research


Insufficient classes on clinical trial topics (especially ICH-GCP) in the current curricula of

relevant Masters degrees

No central registration of investigators with an ICH-GCP certificate from an accredited

institute

No system for accredited ICH-GCP training and assigning accredited institutes


Rigid labour law

Image of industry in the Netherlands is worse than anywhere else in the world, due to

statements by some politicians and the media

Difficult to get on the reimbursement list of the health care insurers with a new compound

GPs are reluctant to prescribe new compounds

On a global scale, Western-European countries like the Netherlands are extremely

expensive

Government

No long-term vision and continuity by government of knowledge economy

Insufficient collaboration between the departments of VWS and EZ: the government should

aim to better link economic, scientific and health care activities

Section 1: Analysis

26

2.3 Opportunities


Assist investigators with the preparation and collection of submission packages for METC

approval and local feasibility assessment

Further professionalize management at the CCMO, in order to improve the clinical research

process in the Netherlands

Regulations

Adjust the requirements for trials involving orphan disease, paediatrics and gene therapy to

mirror those in other EU countries (but no stricter) so that the Dutch clinical research

environment can benefit from both the excellent networks in place and the status of these

studies as pre-eminently interesting for its more unique technical knowledge and

experience

Infrastructure

Further develop the trend of establishing research desks in hospitals to facilitate the clinical

trial process for industry and CROs.

Create initiatives to improve the clinical research structure at hospitals and create

awareness on hospital boards

Improve patient awareness of the benefits of participating in a clinical trial

Link patient data at a national scale in order to have access to a larger patient population.

Further collaboration of hospitals on a national or regional level in order to have access to

higher patient populations

Improve awareness throughout hospitals of ongoing clinical trials in order to minimize

possibility of missing out on any potential study subjects

Maintain and further improve the excellent position of Dutch clinical research

(infrastructure and high quality investigators) with respect to the more complex, early

stage trials, that need scientific and technical input, since several expected trends in clinical

research require this type of service (oncology, trials with small indications) (development

of specific innovative drugs) (personalized medicine, translational medicine etc.)

Make use of the excellent existing network (MRCN) in place for paediatric trials

Maintain the Netherlands’ strong position with respect to the wide availability of key

opinion leaders

Strengthen the position of organizations like ACRON and DCTF towards government, CCMO

and other authorities, in order to influence decisions and to implement improvements for

the clinical research environment

Maintain the Netherlands’ excellent position and setting for Phase I trials (expectations are

that more Phase I knowledge is insourced)

Section 1: Analysis

27

Stimulate collaboration between different players in research. The Dutch Medicines Days

organized by the “Federatie Innovatief Geneesmiddelen Onderzoek Nederland” (FIGON) is

an important initiative in this respect.


Arrange central registration and the obligation to pursue training at an accredited institute

that provides appropriate (e-learning) training in ICH-GCP and create a system for

assigning accredited institutes

The success of the BROK-course is an opportunity to market the increase in the quality of

the Dutch clinical trial environment to other countries

Further improvement of ICH-GCP training and compliance


Improved collaboration between the departments of VWS and EZ to make the Netherlands

a more attractive country for investment

Create incentives for parties that are useful to the Dutch clinical research environment

Government

Nurture a knowledge economy principle

2.4 Threats

METC approval process

Although it might be difficult to remain competitive on a global scale for certain types of

trials (see below), at a European level it is still important to maintain and improve our

competitive position. The slow METC approval process may result in the situation that

pharmaceutical companies will move to other European countries where there is faster

patient recruitment due to a more efficient METC approval process (signs of this

development are already visible: Belgium is performing much better in this respect)

Further harmonization of the METC approval process would immediately jeopardize the

competitive position for Phase I trials in the Netherlands, since this would entail the

levelling out of timelines at a European level. With the Phase I unit of PRA as the largest

employer in clinical research in the Netherlands, this is a direct and serious threat to our

clinical research environment

The further harmonization of the METC approval will make for additional layers of delay

Regulations

The stringent regulations regarding gene therapy and paediatric studies are a missed

opportunity, since Dutch investigators are and infrastructure is, well-equipped to handle

these highly scientific studies. Currently, the most interesting studies in this scientific area

are conducted in other European countries.

Section 1: Analysis

28

Infrastructure

The lack of interest by specialists of participating in phase IIa studies will eventually lead to

a situation where this type of research will disappear

The absence of a research friendly mind-set in our key opinion leaders is a threat: in such a

global environment where specialists in other countries are increasing their knowledge and

reputation there is a possibility that this might lead to a shift to countries where key

opinion leaders are well-equipped and eager to participate at the operational level of the

trial

Emerging markets

Sponsors are increasingly basing their decisions upon where to conduct their clinical trial

on hard and actual figures regarding patient recruitment and the potential future market.

For less complicated confirmatory studies the research environment is also available in less

expensive countries, where the sponsor has access to a large naïve patient population. Due

the limited size of the patient population (determined by the size of the country and high

standard of care) and the small potential future market it is impossible for the Netherlands

to compete with these countries on this type of trials

There is a risk that the Dutch clinical trial environment may underestimate the speed of

development in emerging markets. It is crucial to further develop the strengths of the Dutch

clinical trial environment, in order to remain competitive

Globalization

Departure of the R&D activities of industry will lead to loss of collaboration on joint

ventures between industry and academic hospitals

Due to the departure of the local R&D units of large pharmaceutical companies, it is likely

that talented investigators are leaving the country. Since the quality of these investigators is

one of the current environments’ biggest strengths (and if disregarded would amount to a

loss of investment in education) it is crucial to sustain the position of the Netherlands as an

appealing location in which to perform scientifically interesting clinical research.

Section 1: Analysis

29

3 Recommendations

In addition to the recommendations made in the “Opportunities” section above, please find

below a summary and completion of the recommendations for the improvement of the clinical

research climate in the Netherlands. This section will provide recommendations that can be

used as a starting point for further assessment at a more detailed level on how to approach and

implement the required improvements.


Make all required efforts to maintain the Netherlands’ competitive position for Phase I

trials on the global stage. This means that the ACRON and DCTF have to make a serious and

concerted effort to strengthen their position in relation to organizations that can influence

this decision, such as the CCMO and EMA and make a solid, united stand in regards to this

topic

Improve the METC approval process, by implementing clear timelines for the local

feasibility committees (with Belgium as an example), invest time in collaboration with

hospital boards, support investigators with the preparation of the submission package and

further support and stimulate the national committee that streamlines the process for

METC approvals

Regulations

In order to avoid a disproportionate administrative burden and discourage investigators, it

is recommended that there is an attempt made to differentiate in the regulations for clinical

research (for investigators and pharmacies) between (smaller) investigator initiated trials

and (large) industry sponsored trials

The implementation of the EU CTD has increased bureaucracy in all EU countries. It would

however be beneficial for the competitive position of the Netherlands to assess whether

there are administrative processes and regulations that can be adjusted in such a way that

bureaucracy will decrease (while respecting EU guidelines) and the Netherlands can

become a more attractive country for clinical research

Adjust requirements for trials involving orphan diseases, paediatrics and gene therapy to

those requirements in other EU countries (but not stricter) so that the Dutch clinical

research environment can benefit from the fact that they are very well equipped for this

type of study

Infrastructure

Hospital should receive incentives from government and industry to support the

establishment of research desks

Section 1: Analysis

30

Create initiatives that can improve the clinical research structure at hospitals and create


Improve the general perception of industry sponsored trials within hospitals, so that it

becomes more interesting for investigators to participate

Take advantage of and embrace the development that, the emphasis will shift to the earlier

phases of clinical research for cost efficiency reasons, sell our expertise on translational

medicine, predict pharmacodynamic effects and other early phase research, because this is

one of the Netherlands’ biggest strengths

Further strengthen the Dutch MCRN network and draw international attention to this

network in order to increase the number of paediatric trials in the Netherlands which

contribute to increased experience

Create opportunities for interesting scientific research in the Netherlands and attract R&D

from industry in order to hold on to the Dutch key opinion leaders

Make an effort to improve the research-unfriendly mind-set of many key opinion leaders in

order to remain competitive with countries that are developing fast and will be able to

provide alternative knowledge and expertise. On top a of that, a research-friendly mind-set

should be developed in order to remain attractive for the industry

Stimulate further collaboration between industry and academic hospitals

Patient access

Link patient data nation-wide and promote and develop collaboration and networks in

order to have access to a larger patient population

Strengthen and improve existing patient networks in the Netherlands and make use of

existing patient organizations

Encourage awareness at hospitals of ongoing clinical trials in order to not miss out on any

potential research participants

Increase patient awareness of the benefits of participating in a clinical trial

Invest in relationships with GPs in order to facilitate patient access for GP indications


Encourage universities to incorporate classes on clinical trial topics (especially ICH-GCP) in

the curriculums of relevant Masters degrees

Assign accredited institutes that can provide ICH-GCP training by way of e-learning and

centralize the registration of training certificates

Further support initiatives that improve ICH-GCP compliance and awareness of the Dutch

investigators

Section 1: Analysis

31

Use the current and ongoing improvement of ICH-GCP training and compliance (e.g. BROK-

course) to market the quality of Dutch clinical research to other countries

Organizations

The organizations in the Netherlands that are working on the improvement of the Dutch

clinical trial environment (Nefarma, DCTF, ACRON and Life Sciences and Health) should,

wherever possible, join forces in order to effectively identify existing problems and find

solutions in an coordinated manner and to effectively implement improvements (as an

example see for instance the “The Initiative” in Belgium: www.theinitiative.be)

DCTF and ACRON should create a stronger position in relation to the CCMO, government

and other authorities at a local or international level in order to exert more influence on

decisions that directly affect the state of the clinical trial industry in the Netherlands


Improve collaboration between the departments of VWS and EZ in order to link economic

activities with scientific and healthcare activities. Furthermore, the government should try

to create interesting opportunities for the industry (and thus for the Dutch research

environment)

Provide financial incentives to industry in order to strengthen the Dutch clinical trial

environment

Government

The Netherlands should differentiate itself from other countries by offering a high level of

infrastructure and services with support from the government, with Switzerland as an

example

The government should create a long term vision for establishing and stimulating our

knowledge economy

The government should carry out more inspections in order to increase the quality level of

clinical research in the Netherlands. However, this should be done in accordance with the

rationale behind the regulations and not simply by stringently following strict regulations

The government should make an effort to improve the image of the clinical trial industry by

creating a better understanding, awareness and appreciation of the positive aspects of

sponsor initiated clinical research, from which everybody benefits (such as improvement of

our standard of care)

Globalization

Create improved collaboration with other EU countries and together strengthen the

position of Europe as a clinical trial region. It is better to look for international

http://www.theinitiative.be/

Section 1: Analysis

32

collaboration and let other countries learn from our specific strengths than to strengthen

our position as a single country

Improve international collaboration in order to maintain a participating position as a

smaller country in the clinical research environment

Section 1: Analysis

33

SECTION 2: INTERVIEWS

T. van Gelder, MD PhD (Erasmus MC)

35

T. van Gelder, MD (Erasmus MC, Rotterdam)

27 August 2010, Rotterdam

Name: Teun van Gelder, MD

Organization: Erasmus Medical Centre, Rotterdam

Title: Internist - nephrologist and clinical pharmacologist

Description of the Organization: The Erasmus MC is the largest of the eight university

medical centres in the Netherlands. The core activities of the Erasmus MC are patient

healthcare, research and education. Scientific research has become one of the most important

activities of the Erasmus MC. Currently, the Erasmus MC is ranked as one of the forty best

research institutes in the World.

Professional background and role in organization: Since 1988, Teun van Gelder has worked

as an Internist - nephrologist and clinical-pharmacologist at the Erasmus MC and has been

involved in clinical research since 1990. Since august 2010 he has been working as a Professor

in Clinical Pharmacology at Erasmus MC. Teun van Gelder is Vice-Chairman of the METC of the

Erasmus MC (6 years), and chairman of the BROK-course1 committee.


The general perception in the Netherlands is that the METC approval process is slow. However

the situation is comparable in other countries. A substantial development to improve the

process has recently occurred: whereas in the past all hospitals participating in a clinical trial

wanted to make their own assessment, nowadays one METC is making the assessment and the

other hospitals only make an assessment on the local feasibility assessment and patient

information. A national committee has been established to further streamline this process. The

national committee helps by assisting investigators to develop a good quality of informed

patients willing to consent and by attempting to facilitate the collaboration of the METCs. At

the Erasmus MC, the local feasibility assessment is not carried out by the METC anymore, but

by an independent committee. This process has facilitated the METC process tremendously.

The time required to receive METC approval could be further improved, but obtaining the

METC approval is often not the time consuming factor (although it is usually presented that

way). We should, also look at the time taken between the METC approval and the first patient

being enrolled in the trial, which is sometimes very long (often six months or more). This delay

1 Basiscursus Regelgeving en Organisatie voor Klinisch Onderzoekers (BROK)

http://www.linkedin.com/companies/erasmus-mc

http://www.juliuscentrum.nl/julius/Portals/4/BROK%20cursus%20UMC%20Utrecht%20Brochure_6_Jun%202010.doc


36

is often due to the investigator (too busy, no motivation), or alternatively the sponsor or CRO

can be guilty of delaying the process.

A central European METC is at this stage not desirable. It will be difficult for METCs in the

Netherlands to accept the assessment of METCs in countries with less experience in clinical

research and it will further delay the process.

Effects implementation EU CTD

The regulations in the Netherlands were already adequate before the implementation of the EU

CTD. The implementation of the 60-day timeline for the METC approval process is an

improvement. A better compliance with ICH-GCP is visible, which is the result of further

professionalization of the research environment stimulated by the EU CTD. However, the

implementation also created a lot of administrative burden. It is not always clear how patient

safety benefits from this.

The extensive reporting requirements make it more difficult for an investigator or an METC to

keep a good overview, and derive the relevant information. Data safety monitoring boards are

better equipped to control the many reports and make the right assessments. This is beneficial

as the investigator and METC can rely on them. At the EFGCP (European Forum for Good

Clinical Practice) meeting in Brussels there was a possibility to discuss these topics.

Unfortunately, the attendees consisted mostly of regulators and not investigators, leading to

insufficient emphasis on discussions to reduce bureaucracy. Of note, the report of the

European Science Foundation is very helpful2. It provides good recommendations for reducing

bureaucracy, for instance by differentiating between low-risk and high-risk research.

Data Protection

The effects of the Data Protection Directive are not yet visible. Certain data protection issues

that the hospital have to deal with, can include requests from the sponsor of a clinical trial who

wishes to have access to the source data, and even wishes to receive copies of the patient files,

which is of course not acceptable.

Negotiating site agreements

Contract negotiations tend to be slow as the contracts submitted to the legal department of the

hospital often are based under foreign law, and may require changes related to the local

situation. Sometimes delays are also caused by unreasonable demands of the sponsors. Often

the agreements are submitted at the end of the METC approval process.

2 European Science Foundation (2009) – Forward Look - Investigator-Driven Clinical Trials


37

A standard clinical trial agreement as proposed by the CCMO will only result in time reduction

if the template is supported by a substantial platform of all parties involved in clinical research

in the Netherlands (local subsidiaries of the pharmaceutical companies, the CROs and the

academic hospitals), similar to the UK approach. A standard template that is created

unilaterally will not be accepted by all parties involved and will not reduce the negotiation

time.

The quality of clinical research in the Netherlands

The Netherlands is known internationally for its high quality education and its scientifically

well trained and high quality investigators. There is industry consensus in the strengths of the

Netherlands: reliable data, timely reporting, minimal fraud etc. In addition, in the Netherlands

there is good communication between the pre-clinical and clinical part of research. It is

important for pre-clinical and clinical researchers to be able to have thorough discussions on

their collaboration and transition of the research phase.

Recruitment and motivation of investigators

Sponsor initiated later phase clinical research is not always very interesting for an investigator.

Especially as the bigger pharmaceutical companies have in-house expertise and do not ask for

a lot of input from the investigators. Sometimes (smaller) pharmaceutical companies ask for

some input through advisory boards or special interest groups. The pharmaceutical companies

are often less interested in the pre-clinical part of the study. In order to make conducting trials

appealing to investigators, in the Erasmus MC the investigators often negotiate the possibility

to also set up sub-studies (and ask for sponsoring) that create a link with the pre-clinical phase.

This enables them to obtain answers to questions that are interesting to the investigators.

Investigators can often not participate in the publications of sponsor initiated multi-centre

trials: in many cases only e.g. the top 10 recruiters will receive this privilege. Financially it is

also not very interesting: a reasonable reimbursement is provided for the services, but with the

increased regulations a lot of resources are needed (research nurse etc.).

In general, Dutch investigators are still enthusiastic to participate in clinical trials, and want to

participate in the world-arena. There can be big differences between the different

departments: some departments are very active in clinical research and have a good link with

industry, whereas other departments are not interested (it is often “a matter of tradition”

within the department). Financially there is no conflict of interest since the remuneration

always goes to the relevant department of the hospital and not directly to the investigator.


38

Training and education investigators

Erasmus MC is paying a lot of attention to ensure proper opportunities for training people to

become a liaison between basic clinical research and the lab, for example by offering a Master’s

degree to its students where they are trained in this task. The University of Groningen is

offering the GUIDE course (“Good Research Practices: GCP and GLP) in which they combine the

pre-clinical and the clinical phase in research (see above). The BROK course plays an important

role in ensuring that investigators are trained in and operate in compliance with ICH-GCP

guidelines.

As the chairman of the BROK-course committee, Teun van Gelder is planning to write an

editorial in the British Medical Journal of Medicine or Clinical Pharmacology and Therapeutics

in order to present evidence that Dutch clinical research has improved in quality because of

this initiative. Investigators from the STZ (Association of Teaching Hospitals) hospitals are also

interested in the course, and can join at the academic hospitals in their area. Unfortunately, in

some of the UMCs, the demand for the course is often higher than the supply.

Infrastructure hospitals

Industry sponsored studies are not supported from within the hospitals, The prestige of

industry sponsored studies is less than studies funded by governmental organizations like

ZonMw and NWO (e.g. Veni, Vidi and Vici beurs). The greater difficulty in obtaining funding, the

higher the prestige. The hospital board does not offer finance support for industry sponsored

clinical research. If the investigator wishes to participate, he has to negotiate with the sponsor

for the reimbursement for the costs and required resources.

A central clinical trial desk that facilitates support for clinical research is a good idea, but in

practice will be difficult to achieve. The more successful departments do not wish to share the

results of their success and their infrastructure with the less successful departments. In the

Erasmus MC, the department that is most successful will get the largest part of the

remuneration. In Maastricht they have established a central clinical trial desk that is funded by

the investigators: the CTCM (Clinical Trial Centre Maastricht). As expected not all investigators

are enthusiastic about this initiative.

Recruitment of study subjects

The Netherlands is a relatively small country, with consequently not a very large patient

population. Since initiating a clinical trial in an additional country is very costly, the industry

often chooses to initiate the studies in foreign countries where more patients are available.

Local R&D units of the industry often “fight” for their country, so that their office is not ignored.


39

Clinical trials in the Netherlands often perform relatively well in respect of the recruitment of

patients. Patients are eager to participate, since they have a lot of confidence in their treatment

by physicians. In order to prepare potential study subjects for the possibility of participating in

a trial, the investigators have good contacts with the patient organizations.

Trends in clinical research

Teun van Gelder totally supports the international development that negative findings need to

be published as well as the positive findings (See e.g. FDA Amendments Act 801). In the

Netherlands Journal of Medicine he has written an editorial on “the importance of reporting

negative findings”3, in which he emphasizes that negative findings are also scientifically

important. Teun van Gelder also advocates that editors of scientific magazines encourage

investigators to divulge that a case study is cancelled for safety reasons.

The effects of globalization

It is likely that with the departure of R&D units like the one from Organon (MSD) to their head

offices, promising scientists and investigators will move to the countries where the industry

performs scientifically interesting research. Some investigators prefer to work in an academic

hospital, because they have more freedom in the choice of the research area (and in such a case

they are not very likely to move abroad). On the contrary , for some investigators it is also very

attractive to work for a pharmaceutical company, since they offer high quality research

facilities and as an investigator you do not have to find external funding.

The role of the Dutch government

It is remarkable that the government did not prevent the acquisition of Organon at the time,

and that they did not try to invest in order to save the R&D unit for the Netherlands. Investing

in Organon instead of selling it would have been more in line with the principle of the

knowledge economy and the investments in clinical research already made. The current

developments at Organon (MSD) are not a big surprise. It is however, difficult to judge if the

government really could have did more, since the interests and objectives of a big company and

the government will always be different.

3 T. van Gelder (2007). The ups and downs of sirolimus in kidney transplantation, and the importance of reporting negative findings. The

Netherlands Journal of Medicine, volume 65 (no. 1), page 7-8.


40

SWOT Analysis

Strengths

Improved METC approval process

High quality education and

investigators

Good clinical research image

(“reliable”)

Good link between pre-clinical and

clinical research

Weaknesses

Administrative barriers involved with

performing a clinical trial

Sponsor-initiated trials are often not

scientifically and financially interesting

enough for investigators, they do also not

get enough prestige

We do have a relatively small patient

population

Opportunities

The BROK course is an opportunity to

sell the improved research quality of

the Netherlands abroad

Nurture the knowledge economy

principle

Threats

Talented scientists will move abroad to

follow the more interesting R&D

activities of the industry

Recommendations

Make industry sponsored trials better respected and appreciated within the hospitals,

so that it becomes more interesting for investigators to participate

Use current Dutch initiatives with respect to ICH-GCP compliance (e.g. BROK-course) to

sell the quality of the Dutch clinical research abroad

P.A.B.M. Smits, MD FFPM (Radboud University Nijmegen Medical Centre)

41


3 September 2010, Nijmegen

Name: Paul Smits, MD FFPM

Organization: Radboud University Nijmegen Medical Centre

Title: Head of the Department of Pharmacology and Toxicology

Internist and Professor of Pharmacology at the Radboud University Nijmegen Medical Centre

(since 1995)

Scientific Director Research Institute 'Nijmegen Centre for Evidence Based Practice'

Chairman 'Instituut Waarborging Kwaliteit en Veiligheid' in Radboud University Nijmegen

Medical Centre.

Description of the Organization: The Radboud University Nijmegen Medical Centre is an

Academic Medical Centre that combines patient healthcare, education and research. The

Radboud University Nijmegen Medical Centre is a top knowledge centre for academic medicine

and health care, and as such also involved in clinical research.

Professional background and role in organization: Paul Smits is an internist at the Radboud

University Nijmegen Medical Centre and in his function as head of the Pharmacology-

Toxicology department, involved in clinical research. His expertise concerns cardiovascular

research and is specifically focused on the stage during which the pre-clinical part of a trial is

transposed to the clinical part (“proof of concept” studies). The studies in which he is involved

are often small-scale investigator initiated studies with a placebo-controlled, randomized study

design. However, he is also involved in later phase industry sponsored trials.


The METC approval process at the Radboud University Nijmegen Medical Centre is very well

organized. Radboud University Nijmegen Medical Centre has its own Commission on Research

Involving Human Subjects, and they are very efficient and perceptive for good arguments and

as such are not a delaying factor in the process.


Implementation of the EU CTD has resulted in greater levels of bureaucracy for investigators.

This is especially true given the fact that (smaller) investigator initiated trials are treated in a

similar fashion to (large) industry sponsored trials with regard to the laws and regulations.

This is a frustrating and discouraging factor. Greater differentiation in laws and regulations,

between different types of clinical research would solve this situation. The same situation

applies to pharmacies (GMP), which are bound by very strict rules of inspection. They are


42

required to have a very complex infrastructure, even in not particularly complex situations. It

would be helpful if, in this case common sense prevails and a differentiation is made in order to

avoid unnecessary delays.

An example here is a study initiated by Paul Smits 2,5 years ago which focused on an

endogenous substance: it has not yet started, due to the extensive administrative and approval

requirements. Obviously safety has to be taken into consideration, but common sense should

also be applied. The risk is, that a lot of time is invested in a scientifically important idea, and

eventually investigators in countries where less strict laws and regulations are in place will

catch up. These countries will be able to finalize a clinical trial on the subject matter before the

Netherlands do.

Negotiation of site agreements

In the past, the negotiations surrounding site agreements were not concluded in an efficient

and timely manner. However, since the Radboud University Nijmegen Medical Centre opened a

valorisation department with its own lawyers (possessing industry knowledge), this process

has improved considerably and has become more professional (also with respect to patent

protection etc.).


The Netherlands has a good reputation with respect to clinical research, due to high (scientific)

investigator quality and the presence of many Key Opinion Leaders. The Netherlands is known

for its high level of education and high quality universities. In addition, the Netherlands is

perceived as a country that is down to earth and takes the reliability and integrity of the study

data very seriously.

Costs

For the industry the Netherlands is an expensive country: the costs are relatively high due to

the many layers of bureaucracy and the high salary level in the Netherlands.


Sponsor initiated trials are not very interesting if there is no possibility for scientific output or

publication. The money earned with a clinical trial is not a motivating factor for an investigator:

usually the workload is relatively high and the money comparatively low. Even in a multi-

centre international setting, such a trial is unlikely to scientifically interesting. unless an

investigator participates as a Key Opinion Leader for a certain indication.

The industry is also sometimes interested in small-scale proof-of-concept studies: they can test

a small patient population and get an indication of the outcome of a clinical trial, which can


43

save them money in the long term. This type of study is also often scientifically more

interesting for an investigator.

Whether an investigator prefers to participate in a more technical study or a more applied

clinical trial with certain endpoints, eventually depends on the specific interest and

possibilities of the investigator concerned. Universities will generally prefer more ground-

breaking research, whilst the larger hospitals are usually interested in applied clinical trials, as

they do not have access to the required techniques and setting for proof-of-concept studies.


All investigators (doctoral students and their mentors) involved in clinical research at the

Radboud University Nijmegen Medical Centre are obliged to participate in the BROK-course, in

order to ensure solid knowledge of ICH-GCP guidelines. The training requirements for clinical

drug research are perceived as disproportionate by the investigators compared to other types

of research and therefore sometimes have a discouraging effect.


In general, the internal support from hospitals for the performance of clinical trials is not

substantial. At the Radboud University Nijmegen Medical Centre, effort is made to improve the

situation through the establishment of the CRCN (Clinical Research Centre Nijmegen). CRCN’s

objective is to create a platform where a lot of expertise, facilities and support is provided for

conducting a clinical trial. The costs for making use of the CRCN are met by the department

concerned. The investigator has three choices when performing a clinical trial: a) arrange the

trial individually, but ensure that it is performed in accordance with ICH-GCP (the hospital

board will check compliance by way of internal audits), b) perform the trial completely with

CRCN or c) perform the trial individually, and make use of CRCN expertise.

In addition, the Radboud University Nijmegen Medical Centre has a gratuity system that

stimulates research on the basis of performance: if an investigator at the Radboud University

Nijmegen Medical Centre has shown its (scientific) contribution to the hospital, by way of

publications, mentoring promotions and arranging funding for the hospital, an investigator

gets the possibility to become a Principal Investigator (PI) at the hospital. In such a case, the

department will receive funding from the hospital in order to free up time for the PI to perform

research and further professional development.


The recruitment of patients for a clinical trial is often underestimated and are almost never in

line with projections. Important factors are that, there exist extensive inclusion criteria


44

required by the protocol, and investigators are often fishing in the same patient pool. The

recruitment of healthy volunteers is a lot less complicated, due to advertising and the

interesting payments available for volunteers and also the fact that with this type of study the

exclusion criteria are more significant.

The Radboud University Nijmegen Medical Centre owns a database containing patient data,

therefore they can contact the doctors from the hospital to enquire if patients can be

approached for a certain clinic trial. This is a development that can be further improved by

better IT support and input. In this perspective “Parelsnoer” is worthwhile mentioning: an

initiative between the academic hospitals to set-up a nation-wide bio-bank. This could also be

achieved for patient data. The “Interuniversitair Cardiologisch onderzoeks instituut” (ICIN) is a

good example of how that could work: they collaborate nation-wide in order to have access to

the required large number of patients for a clinical trial. The Radboud University Nijmegen

Medical Centre has a department for first line medicine that has an excellent network for

clinical research with general practitioners in the area of Nijmegen, which can be used as a

source for study subjects.

The image of clinical research (“guinea pig” idea) when participating in an industry sponsored

trial sometimes plays a role in patient decision making on participation. For investigator

initiated trials and studies with healthy volunteers this plays a less significant role.

Collaboration industry, CROs and academic hospitals

The interaction between industry and universities is good. The Radboud University Nijmegen

Medical Centre is in contact with Organon (MSD) at different levels. The Centre for

Translational Molecular Medicine (CTMM) in Eindhoven and TI Pharma in Leiden are both

joint ventures between the government, the industry and the universities. The government

stimulates the collaboration between industry and universities. This initiative is dependent on

the input of the R&D units from the industry, which is now only Organon (MSD). A next

generation of government initiated projects are not very likely, now that the R&D unit of

Organon (MSD) has closed down and been transferred to the United States. Maybe now we

should explore opportunities at a European level. This will of course be more complicated if the

Netherlands has to compete with other countries and face different governmental interference.

Another option is to seek collaboration with the other UMCs and perform study prepare

protocols and SOPs together etc. This could prove stimulating for centrally organized clinical

research.


45


The development of technologies with artificial organs (e.g. artificial kidney and liver) can

generate important information at an early stage, so that it can be tested on human beings at a

fairly early stage. Another trend in clinical research is personalized medicine: clinical research

will be based more on polymorphism and specific patient features. There has been a shift in

discussions on how a clinical trial should be arranged: e.g. whether responders and non-

responders should be looked at separately and if kinetic polymorphisms should be included.


Because there are many options on a global scale, it has become less interesting for the

industry to perform clinical trials in the Netherlands, because of the high costs (see above). It is

only a matter of time before other countries will improve in quality and industry driven

research will move abroad to more cost efficient countries.

For investigator initiated research, the situation is different as the knowledge and expertise

required for this type of study is not so easily available in the emerging markets. The only

danger is that because of excessive regulations this type of research is discouraged. The other

important effect of globalization on the industry, is that with the departure of Dutch R&D units

to head offices abroad, this leads to very serious negative impact on the clinical research

environment in the Netherlands.


The fact that the appropriate governmental departments did not communicate with Hans

Wijers on the importance of the knowledge economy and the effects that the acquisition of

Organon by Schering Plough would have in that perspective, was a missed opportunity. We

should be able to trust the government to make the right decisions in this type of important

strategic situation, and now there is little they can do. The only opportunity available to save

the R&D unit from Organon (MSD) is through acquisition by another large pharmaceutical

company.

In general, the Dutch government could play a role in the improvement of the clinical research

environment by down-grading the laws and regulations to an acceptable level, so that the

Netherlands remain competitive. In addition, The Dutch inspection could be more active in

order to increase the level of clinical research, provided that the inspections are done by the

basic principles of clinical research and not marginal regulations.


46

SWOT Analysis

Strengths

Good image investigators

Many Key Opinion Leaders

Good universities

Reliability and integrity of the research

climate

Valuable interaction universities and

industry

Weaknesses

Bureaucracy

Lack of differentiation in regulations for

different types of research

Opportunities

METC approval process is improved

ICH-GCP compliance investigators is

improving (BROK-course)

Support from hospital is improving

Link patient data nation-wide and other

nation –wide recruitment initiatives and

networks in order to have access to a

larger patient population

Personalized medicine

Shift to pre-clinical and early phase trials

Threats

Cheaper countries also gradually provide

good quality

Loss of expertise from the industry

(Organon)

Loss of collaboration with the industry

(Organon)

Investigators are not very interested in

international trials

Patient recruitment underestimated

Recommendations

Differentiate in the regulations for clinical research (investigators and pharmacies)

between (smaller) investigator initiated trials and (large) industry sponsored trials

Reduce regulations in order to become quicker and cheaper and therefore more

competitive

Link patient data nation-wide and create collaboration and networks in order to have

access to a larger patient population

More inspections by the government in order to increase the level of clinical research in

the Netherlands

F.H. Bosch, MD PhD (Rijnstate Hospital)

47

F.H. Bosch, MD (Rijnstate Hospital/Alysis Zorggroep)

6 September 2010, Arnhem

Name: Frank Bosch, MD

Organization: Rijnstate Hospital/Alysis Zorggroep

Title: Internist

Description of the Organization: The Rijnstate Hospital is part of the Alysis zorggroep and a

member of the Association of Tertiary Medical Teaching Hospitals (STZ – samenwerkende

topklinische ziekenhuizen). Besides the treatment of patients, Rijnstate Hospital focuses on

applied clinical research and innovation in healthcare.

Professional background and role in organization: Frank Bosch has been working as an

internist at the Rijnstate Hospital since 1989. Primarily, he is involved in investigator initiated

research, which results in high standard publications once every 2 to 3 years. Occasionally he

will also participate in sponsor initiated clinical trials, but only when there is an added

scientific value. The clinical research performed in the hospital is principally Phase II to IV

research. There is not a great deal of drug related research that directly correlates to the

patient population for whom he is responsible (i.e. intensive care patients). Frank Bosch was

previously manager of the “leerhuis” of the Rijnstate Hospital, the core objective of which is to

facilitate education and development for the hospital and its staff. He is a board member of the

DCTF and president of the Dutch Internists Society.


At the Rijnstate Hospital, the local approval process has been improved substantially. There is

a regional METC and a separate local feasibility committee. The duration of the METC approval

process is not usually the principal delaying factor. The time that elapses between approval

and enrolment of the first patient in the study takes a substantial amount of time in the clinical

trial process. However, this parameter is never measured or mentioned in this perspective.

Implementing a European METC approval will only add additional administrative layers and

thus increased bureaucracy.


There are no substantial changes visible since the implementation of the EU CTD. It is also

currently difficult to determine how the implementation will eventually influence the Dutch

clinical research environment, since the regulations have not yet been executed in all of its

areas. The only evident change has been the increase in administrative burdens.


48

Standardization of clinical trial documents

Unambiguous and good quality patient informed consent forms will improve the conduct of

clinical trials, since it will facilitate improved patient inclusion.


The Netherlands is a small country with a relatively high number of qualified individuals and

organizations. The Netherlands has a significant number of useful collaborations in place and

an excellent health care system. The Netherlands is performing very well in terms of clinical

research, when considering the amount and level of research carried out and the number of

high quality publications produced by Dutch investigators. The quality and education of the

investigators and study nurses is excellent.

Costs

The costs of a clinical trial are not deemed as important by a sponsor as the opportunity to set

up the right infrastructure and research process for their clinical trial.

Motivation of investigators

Payments made to an investigator by the industry, for clinical research, are reasonable in

relation to the services provided (as required by ethical norms) but, are not the most

important incentive for the participation of the investigator. The scientific value of a study is in

that sense more decisive.


In the past it proved a challenge for the Rijnstate Hospital to track all the investigators that

were trained on ICH-GCP. The hospital is now working on a proper registration system for the

training of investigators and has implemented a “teach the teacher” program and an ICH-GCP

course for their investigators.


The conducting of clinical research trials is not supported by the hospital (financially or

otherwise) but instead based on the individual decision of the investigator. The hospital board

is not particularly positive about collaborating with the industry: the perception from the

hospital’s viewpoint is that industry sponsored clinical research is costing the hospital a large

amount of money and the specialist is the party that benefits financially. It often proves

difficult holding the hospital responsible for costs incurred when treating a patient that is

participating in a clinical trial. The question should be: do hospitals have an obligation to

perform clinical research and if so, should they receive payment for providing this service?


49


For successful patient recruitment, it is very important that every member of the relevant

department (maybe even every member of staff at the hospital) is aware of the existing and

ongoing trials. For the type of studies in which Frank Bosch is involved, recruitment of patients

takes place at the intensive care unit. In his department, everybody has the same objective: all

patients are assessed to determine if they are a viable potential participant for the study.

Recruitment is, for instance, more complex for a hypertension trial at a polyclinic: usually not

all doctors working at the polyclinic are involved in the relevant clinical trial and the

completely different authorization structure for making the assessments can prove

problematic. Prospective patients for the clinical trials at the Rijnstate Hospital are usually not

recruited through referral by the first line of care.

The willingness to participate in a clinical trial depends on the study type (it is, for example,

easier to recruit patients for comparative study of two registered compounds than for an

antibiotics trial). The negative image of clinical drug research and a lack of awareness about

the benefits of participating in a clinical trial, influence recruitment.


In the Netherlands we have a strong position as regards clinical research, due to of our

excellent networks. Both the cardiology and gynaecology networks are extremely good and

hospitals are collaborating on clinical trials at a national and regional level. Examples are the

dialysis research that is performed by the Rijnstate Hospital together with the VU, the

collaboration of the Rijnstate Hospital and the Radboud University Nijmegen Medical Centre on

different trials and the PROPATRIA-trial that was done with through the collaboration of 40

hospitals in the Netherlands. This is an important feature of the Dutch clinical trial landscape

that could be further developed to strengthen its position. The collaboration between industry

and universities is seriously impacted by the departure of the R&D unit of Organon (MSD).

Many initiatives that were ongoing between Organon (MSD) and the universities will now

disappear.

The value of Dutch organizations

The initiative to facilitate dialogue between the hospital boards and the pharmaceutical

companies lead by the DCTF has proved successful. The hospital boards are often not exposed

to the benefits of performing industry sponsored clinical trials and it would be of added value

for the clinical research environment in the Netherlands if they collaborated with industry

more effectively and often.


50


A new development is that of tailor-made medicine: it involves pharmacogenetics and requires

a high standard of technological environment, therefore proving interesting for countries in

Western Europe. The central concept is that the genetic profiles of the study subjects are

matched with the profiles of the patients who will subsequently have to use the medicine. The

expectation is that the number of drug takers in the Netherlands will increase. It is important

that we facilitate the right infrastructure that will be able to accommodate and stimulate such a

development. Furthermore, the focus of clinical research in the near future will depend, to a

large extent, upon the personal interests of the investigators.

The areas of attention that were determined by the Rijnstate Hospital last year were vascular

care, oncology and immunology. The hospital also hopes to maintain its position as the number

one hospital in Europe, in the field of bariatric surgery. In the future it is important to focus on

international collaboration opportunities and to ensure the continuance and establishment of

political ties with other countries. Research institutes might spring up in years to come that

place a greater focus on hospitals than countries.


It might currently prove very appealing for industry to look towards cheaper alternatives in

other countries. Such a shift of clinical research to the emerging markets will not be a long term

development however: in 5 to 10 years the costs in these countries will have increased and the

Netherlands will again be more competitive with respect to costs. Large scale cardiovascular

intervention studies are migrating to countries that are able to process large numbers of

patients within a short period of time.


The short reigned and limited powers of the Dutch government are resulting in a lack of

continuity and a failure to take responsibility for decisions made in the clinical research and

health care environment. The government is often unaware of the consequences of their

decisions and lacks integrity in their approach (e.g. the decision to cut the salary of specialists

was done at the same time as allegedly wanting to maintain the high level of health care).

The situation regarding Organon (MSD) is a difficult one for the Dutch government to solve. If

the government wishes to invest in the R&D unit, the unit should be able to continuously

provide added value for the clinical research environment in the Netherlands and should

create even tighter connections with universities.


51

SWOT Analysis

Strengths

High number of qualified investigators

Excellent health care system

Excellent networks (e.g. cardiology and

gynaecology)

Numerous collaborations between the

hospitals at a national and regional level

Weaknesses

Hospital boards have a negative

perception of sponsor initiated clinical

research

Lack of continuity evident in initiatives

from the government to stimulate the

knowledge economy

Opportunities

Further improve ICH-HCP training and

compliance of investigators

Improve collaboration between the

industry and the hospitals

Improve awareness throughout hospitals

of ongoing clinical trials, so that all

patients visiting the hospital are

“screened” on their potential

participation

Improve awareness of benefits of

participating in a clinical trial

In the long term the costs of the

emerging markets will not be as

competitive as they are now

Threats

The closure of the last R&D unit from the

industry in the Netherlands will

jeopardize many valuable initiatives

between industry and the universities

Recommendations

Further improve ICH-HCP training and compliance of investigators

Further improve collaboration between industry and universities

Create better collaborations with other EU countries and together strengthen the

position of Europe as a clinical trial region. It is more advantageous to look for

international collaboration and let other countries learn from our specific strengths

than to strengthen our position as a single country


52

Increase awareness at hospitals on ongoing clinical trials and incorporate the clinical

trial process into the hospital culture

Increase awareness of the benefits of participating in a clinical trial

O.B. Jochems, MD (MediServ)

53


25 August 2010, Eindhoven

Name: Odette Jochems, MD

Organization: MediServ

Title: CEO

Description of the Organization: MediServ was the first Contract Research Organization

(“CRO”) established in the Netherlands and was founded thirty years ago (1980) by Dr. Jan

Janbroers. MediServ is a small, full service CRO, involved in phase II, III and IV trials and

provides assistance for Phase I trials in different countries in Europe. The monitoring by

MediServ takes place in the Benelux. Through the membership of the Pharmaceutical Services

Network “PSN” (a network of CROs in Europe) these services are also provided across Europe,

Africa and the US. Throughout its lifespan, MediServ has performed trials in many different

indications, such as arthritis and associated rheumatic disorders, cardiology, CNS, medical

devices, NSAIDs and urology. MediServ was one of the driving forces behind the establishment

of the ACRON (Association of Clinical Research Organisations in the Netherlands) and is a co-

founder of the above mentioned PSN network.

Professional background and role in organization: Dr. Odette Jochems is a general

practitioner by trade and joined the company in 1982. She started out as a field monitor, was

later a CRA and Project Manager, and in 1991 she became CEO of the company. She continues

to work as a general practitioner.


The biggest single weakness in the Dutch clinical trial environment is the slow METC (Medisch

Ethische Toetsings Commissie) approval process. Dr. Jochems has observed a clear difference

between the process and timelines employed by the Dutch and those used by the Belgians. In

Belgium, submissions to the local METCs have to be made simultaneously and local METCs

must provide their comments to the central METC within 30 days of submission. If the local

METC fails to submit the required documents within this timeline, the central METC will not

consider it for participation in the study. The central EC does not allow the local METC to

provide comments on anything other than patient information and the local feasibility of the

trial. As a result, in Belgium, the METC approval process is always finalized within two months

of the simultaneous submission to local METCs.


54

In the Netherlands, regulations are in place regarding the timelines. However, local feasibility

committees are, besides checking patient information and the local feasibility, also interfering

with the protocol. In the opinion of Dr. Jochems the committees do not feel any pressure to

abide by the timelines. The Netherlands participates in an international clinical trial

environment within competitive enrolment conditions. Often the inclusion period will end with

only a few patients enrolled in the Netherlands, and in the worse cases, ends with sites that

have not even been initiated yet. As a result, the sponsors of clinical trials are beginning to

ignore the Netherlands when making a selection of countries in which they wish to perform

their trial. The sponsor in such case may still be interested in a Dutch Key Opinion Leader

taking a position in a Steering Committee, but, the actual research is performed elsewhere.

A solution could be to implement the same approach as used in Belgium, and provide the

central METC with the tools to put pressure on local feasibility committees in order to better

control the timelines. If the situation is not improved soon, the Netherlands will lose a lot of

business to other countries and risk its competitive position in Europe. Making the METC

approval process less time consuming will improve the Dutch clinical trial climate

considerably.

Effects implementation EU CTD 4

Dr. Jochems has not observed negative effects from the implementation of the EU CTD. In her

experience, the stricter requirements for trials paediatric trials and those involving orphan

disease, do not influence the clinical trial environment in the Netherlands.

Data Protection

The impact of the new data protection requirements further to the European Data Protection

Directive are not yet visible. Other countries in Europe are focusing more on compliance in this

respect: e.g. in Germany the Patient Informed Consent includes a large section on data

protection. However, in the Netherlands this is not (yet) the case.


There is no need for the further standardization of clinical trial documents. A standard clinical

trial agreement will often be unhelpful, since US based sponsors that do not have a local

subsidiary in the Netherlands usually insist on using their own template anyway. Further, it is

usually very difficult to influence the hospitals lawyers in the negotiation process.

4Directive 2001/20/EC of 4 April 2001, of the European Parliament and of the Council on the approximation of the laws, regulations and

administrative provisions of the Member States relating to implementation of good clinical practice in the conduct of clinical trials on

medicinal products for human use

http://en.wikipedia.org/wiki/European_Parliament

http://en.wikipedia.org/wiki/Good_clinical_practice


55


According to Dr. Jochems the Netherlands’ biggest strength as a clinical trial country is that is

that historically the country has been renowned for experience, expertise and quality of clinical

research and the availability of many key opinion leaders. In her experience, these factors are

important when a sponsor wishes to perform a clinical trial and this is why they are selecting

the Netherlands for their trials.

Costs

Since MediServ is part of the PSN, Dr. Jochems is aware of the costs of clinical research in the

different European countries. The costs for performing a clinical trial in the Netherlands

compared to other European countries are standard and in line with the costs in Germany. It is

cheaper than performing a trial in the UK or the Nordic countries. However, the Netherlands

remains more expensive than the Southern European countries. Dr. Jochems’ experience is that

costs are not the most important factor for a sponsor, and that the quality of the clinical trial

services are often decisive.


The sponsor often wishes to work with certain names in the field, who can then assist with the

further recruitment of the investigators for the trial. In the Netherlands, you often end up with

the same group of specialists for the same indication. Specialists are often not very motivated

to participate in a trial. Dr. Jochems notices a clear difference in the willingness to participate

in a clinical trial between specialists in Belgium and the Netherlands. Because of the better

economic situation of specialists in the Netherlands they are not eager to spend time on a

clinical trial, unless they are very well paid for it. In Belgium, the specialists need the money to

finance their clinical trial organization.

For studies involving a general practitioners (“GPs”) it also proves difficult to recruit

investigators. The GPs are too busy with all their administrative obligations. For them,

participation in a clinical drug trial is really an additional burden. In addition, they are usually

not specifically interested in the pharmaceutical industry and innovation.


The educational level of investigators in the Netherlands, is in general, is very good. However,

investigators are often not aware enough of the ICH-GCP requirements. That is why part of the

investigator meeting is always dedicated to ICH-GCP training.

Access to well-trained CRO staff

MediServ was always able to find good-quality staff. However, low turn-over rates hamper

solid general statements on this topic.


56


Currently clinical trial desks are located within the hospitals. The desks can assist in many

aspects of the clinical trial process within the hospital. The research nurses are usually very

well educated. It is beneficial for both the investigators and the industry that they can assist the

investigator and take care of the daily tasks. This in general leads to high quality data. It is also

easier for companies to contact the research clinics: the investigators often have busy

schedules and the research nurse can act as a first point of contact for other parties.

Clinical trial desks can also play a role in the site agreement negotiations: the lawyers at a

hospital often do not feel a sense of urgency when reviewing the site agreements and it is very

difficult to contact them directly. Of course their support would make the whole process more

efficient.


The Netherlands does not have access to a big pool of patients because of the population of the

country. In addition, the high level of our health care system hampers quick and easy

enrolment of patients for clinical drug trials. Furthermore, the recruitment of patients is very

difficult if patients have to be taken off their existing treatment plans. Any departure from

existing treatment plans is not welcomed by either the patient or the investigator.

A thorough feasibility study is crucial, focusing on the study design and indication to avoid

producing disappointing patient recruitment rates. When in doubt, a site should not be

initiated, since it could result in the loss of a large outlay if subsequently no patients are

involved.

Patient networks are not very helpful, since they only collaborate within their own pool of

acquaintances, and are not accessible to all parties in the industry. For studies with indications

such as flu and bladder infection, where patients can only be found with the GPs, it is better to

collaborate with a Site Management Organization (“SMO”) that has a good idea on the planning,

has good recruitment system in place and has access to a pool of patients through a group of

adherent GPs.


It is helpful to have a clear division of responsibilities between the different players in the

clinical trial industry. Risk sharing enterprises between sponsors and CRO can be difficult in

respect to possible conflicts of interest. However, the interaction between industry, CROs and

academic hospitals is generally are desirable and productive .


57


Organizations such as ACRON, DCTF and Nefarma have benefitted in the clinical trial

environment. Nevertheless, further improvements remains necessary. The organizations

should try and obtain a larger influence with the Dutch government and other bodies that have

authorization to change practices in the clinical trial process within the Netherlands.


The past years cardiovascular studies were very popular and now oncology and paediatric

trials have become more important for the industry. Oncology trials in the Netherlands have

been especially successful due to the great infrastructure and governance in this area.


The effects of Globalization highlighted by Organon (MSD) is a by-product of the acquisition of

Dutch companies by foreign pharmaceutical companies. The foreign companies are moving

their R&D divisions to their head offices, where key decisions are made. The local affiliate is

then often only used for selling activities or the executive part of clinical research, which has

little influence on protocol. These activities are not important to a scientist or investigator.

Scientists will be drawn to head office locations that are found out with the Netherlands where

interesting R&D is being undertaken and therefore they will be able to contribute scientifically.

Since our scientific quality is at present one of the Netherlands biggest strengths, This a serious

threat for the clinical research climate in the Netherlands.


The government should act pro-actively and not reactively, as they did with Organon (MSD). If

the government wishes to maintain the knowledge economy found within the Netherlands, the

government should strive to keep important R&D divisions in the Netherlands. At this stage the

government has little influence on the decisions made at the head office of the pharmaceutical

companies.


58

SWOT Analysis

Strengths

The access to experience and expertise

The high quality of clinical research

Availability of many key opinion leaders.

Weaknesses

The slow METC approval process

Opportunities

The oncology governance and

infrastructure is very good: oncology

trials are important research area

Increased use of research desks in

hospitals

Threats

If we do not improve the situation with

the METC approval process, sponsors

will skip the Netherlands as a country to

perform their therapeutic confirmatory

trials in

Our strength comes from the high level

of expertise in our country, however,

globalization may result in a leave of

high level investigators who will move to

the interesting R&D locations elsewhere

in the world (quality will disappear

abroad)

Recommendations

Improve the METC approval process in accordance with the “Belgian model”:

simultaneous submission to the local ECs (ethical commissions) with strict timelines

and requirements for the local feasibility assessment (20 days) and strict timelines for

the central METC (28 days).

A.F. Cohen, MD PhD FFPM (CHDR)

59


26 August 2010, Leiden

Name: Adam Cohen, MD PhD FFPM

Organization: Centre for Human Drug Research

Title: CEO (Director)

Description of the Organization: CHDR is a full service contract research organization (CRO)

that provides a full spectrum of high quality clinical pharmacology services to the (bio-)

pharmaceutical industry. CHDR specializes in data-intensive, early phase, clinical studies

where pharmacokinetic and pharmacodynamic parameters are obtained (studies first-in-

humans PK/PD modelling proof-of-concept). CHDR has a wide-ranging, self-funded research

program where biomarkers are explored for pharmacological responses or other indicators

related to a therapeutic intervention. In addition, CHDR employs medical experts who leverage

their pharmacological know-how to efficiently guide the drug development process.

Professional background and role in organization: Since 1987, Cohen has been the director

of the Centre for Human Drug Research (CHDR). He is professor of Clinical Pharmacology

at Leiden University and has a clinical attachment at the department of nephrology at Leiden

University Medical Centre. He is vice-chairman of the Central Ethics Committee and the

Competent Authority (CCMO) of the Netherlands and European editor of the British Journal of

Clinical Pharmacology as well as a member of the Health Council of the Netherlands and the

Council for Medical Sciences of the Royal Academy of Sciences of the Netherlands.


Slow local feasibility assessments are a delaying factor in the METC approval process in the

Netherlands. This problem cannot be solved by adding further regulations or by implementing

better compliance measures. The basis of the problem can be found in the lack of strategic

overlap between the hospitals and the industry. At the level of the hospital boards and the local

feasibility committees there is no sense of urgency or motivation to participate in clinical trials,

especially if the trial is sponsor initiated. In addition, there appears to be a lack of trust

between the different METCs, which results in a situation where all METCs wish to go through

a complete and thorough assessment procedure at the same level of intensity as was done by

the other METCs.

There is however a gradual progress visible with respect to the local approval process. Levels

of trust between the different METCs are slowly improving and local METCs have come to


60

realize that it is in the best interests of the hospital to make the process more efficient (e.g. the

METC of the Erasmus MC in Rotterdam abolished de “hertoetsing”).


The EU CTD was successfully implemented into Dutch law (the WMO); the interpretation of the

EU CTD was completed in such a way that it did not produce many additional requirements for

performing a clinical trial in the Netherlands. Adam Cohen has been leading the

implementation committee.

The CA approval process in the Netherlands is superior to other such processes anywhere else

in the world; in the Netherlands there no longer exists the dual approval process (thus no

involvement of governmental bodies) as is the case in many other countries. The current

system in the Netherlands can now handle the entire range of disciplines: from gene therapy

studies to very simple generic studies.

A potential threat could arise if European regulations are further harmonized and METC

approval is arranged at a European level. If for example, Dutch investigators need to get

approval in another country in Europe to start their clinical trial, the issues that affect the

obtaining of local approval would then be applicable on a European level. As the situation

slowly improves in the Netherlands, it is recommended that focus should first be placed on

further improvements at a local level.

In general, it would be inaccurate to think that the EU CTD could completely harmonize the

clinical trial system in Europe, since the European countries show substantial differences in

areas such as medical practice and health care systems.

Data Protection

In the Netherlands, the observation of data protection compliance is not yet particularly strict.

There should be a better collaboration between the different players in the clinical research

area to ensure compliance.


The Netherlands is a small country with a relatively high scientific output. The ability to deliver

large quantities of patients may not exist, but the delivering of knowledge and expertise is an

area of strength. The Netherlands also offers a relatively high level of infrastructure: the

hospitals are of homogenous quality and we have excellent universities. In addition Dutch

investigators have a tendency to collaborate on a global scale, which facilitates exchange of

knowledge and visibility of their quality internationally.


61


It is difficult to generate enthusiasm in investigators for participation in therapeutic

confirmatory studies. Direct patient health care is often considered more important and the

investigators usually already have a high work load. Financially and scientifically these types of

studies are not appealing and interesting enough in many cases, especially if there is no

possibility for publication.


The clinical research environment in the Netherlands is known for its high level of scientific

education and the expertise of the investigators. The different players in the clinical research

area should take responsibility for offering the necessary training and education to staff that is

required to perform high level clinical research. The CHDR for instance is starting a course for

nurse practitioners and is continuously training clinical pharmacologists.

Currently, there are insufficient possibilities provided by the mainstream educational system

to properly train and prepare staff for clinical research. If the aim is to create a country where

top clinical research is performed, we should strive for further improvement. There is, at the

moment, too little collaboration and a lack of vision on an integrated country-wide scale with

respect to the education of the required investigators and clinical research staff.


Certified research units in hospitals would improve the clinical trial environment in the

Netherlands. Such units cause the clinical research process in hospitals to be more efficient and

it creates a better facilitation for sponsors and CROs that perform clinical trials in the

Netherlands. If a hospital can create a situation that generates income for future research and

for managing such a research unit, it becomes more appealing for hospitals to participate in

clinical trials, even in the generic ones.


Due to the size of our country and the high standard of care, the Netherlands is not an

attractive country for recruitment large numbers of patients. From that perspective,

performing a therapeutics confirmatory trial in the Netherlands might not appear very

interesting to the industry. However, looking at the data that is available from the CCMO,

around 100.000 patients per year are recruited for clinical research. This number stays fairly

stable and is quite a high number for such a small country.

Recruitment of patients or healthy volunteers at the CHDR is mainly achieved through

advertising. There are no visible effects of the possible negative image of clinical research


62

when recruiting study participants. The infrastructure for recruiting patients could be

improved. Raising awareness in potential patients on the importance of (participating in)

clinical research should in this respect also be taken into consideration.


If the Netherlands would like to become a more important player in clinical research, it must

be ensured that it reaches the status of an excellent clinical research country, with a high level

of expertise and clinical research service. In order to achieve this, industry and the government

have to create a better strategic collaboration between the industry and the investigators.


That there are organizations in the Netherlands that focus on the improvement of the local

clinical trial climate is a valuable state of affairs. The issue is, that often the problems that exist

are not approached in an integrated way and consideration of the complete clinical research

area is lacking. Further, because everybody agrees on what needs to be done differently, there

is no sense of urgency driving solid action. There is no perception of what is required to do

things differently and improve the infrastructure, because no solid analysis has been made of

the existing problems. As a result, the right parties are coming together, but there are no

important results visible.


Adam Cohen does not yet see many innovations that offer the possibility of shifting the clinical

trial process substantially more to the pre-clinical phase. Organ techniques are not

sophisticated enough and are will never be able to provide such a complete picture of a

complex organic model as is provided by animal and human testing. The Dutch clinical trial

environment is very well equipped and developed for this type of pre-clinical and early stage

clinical trials.


Sponsors are now looking at clinical research on a global scale. Regions, such as Latin-America

and Asia, that are more cost efficient, but also are gradually have become sufficiently

developed to perform therapeutic confirmatory trials and are able to deliver large quantities of

(treatment-naive) patients are becoming more interesting for pharmaceutical companies. Since

the Netherlands is more expensive compared to the countries in these aforementioned regions

and has a (relatively) small amount of patients available, it is not very appealing to a sponsor to

outsource this type of research (recruitment of large numbers of patients and straight-forward

data collection) to the Netherlands.


63

Further, the industry links their investments in clinical research to revenues, and as such we

are not a very interesting country as the Netherlands represents only a small market. Adam

Cohen has the opinion that the industry should look at it differently if they wish to improve

clinical research: the Netherlands is an appealing country when it comes to delivering the

infrastructure, the expertise and the knowledge.

Pharmaceutical companies often state that the Netherlands is a research unfriendly country,

since it is difficult for a pharmaceutical company to get its drugs on the market. Mr. Kortlever

from Organon (MSD) has presented this as one of his central arguments when defending the

decision of the Organon (MSD) board to shift the R&D unit to the head office in the US. Adam

Cohen however feels that this argument is not directly related to the fact whether the

Netherlands is a research friendly country or not, and therefore the difficulty for a

pharmaceutical company to get a drug on the market has to be considered in a separate

discussion.


Adam Cohen has the opinion that the governments’ options were limited with respect to

managing the Organon (MSD) situation. Decisions of a large multinational such as Organon

(MSD) with respect to its company strategy are made at the head office and are based on the

requirement to remain competitive. The costs for keeping the R&D unit open via government

investment are simply too high in relation to the potential revenues generated by the R&D unit,

and therefore not worth exploring further.

SWOT Analysis

Strengths

Good CA approval system

Excellent level of scientific education

High quality investigators and research

staff

High and homogenous level of quality of

the hospitals

Cultural tendency to international

collaboration

Reasonable and civilized health care

system

Weaknesses

Local feasibility assessment is a delaying

factor in the METC process

Low motivation for investigators to

participate in generic trials: financially

and scientifically unappealing


64

Opportunities

Do not focus on one aspect of clinical

research, but approach it as one

integrated process. Stimulate

collaboration of the different players in

clinical research, by offering a common

goal

Further develop the trend of establishing

research desks at the hospitals

Threats

Further European harmonization

through the revised EU CTD, which will

further complicate the clinical trial

process

Globalization results in the migration of

quality

Recommendations

Further improve the local feasibility assessment and the participation of investigators

by creating a better strategic overlap of the objectives of industry and investigators

Hospitals should receive incentives and support to install research desks

The Netherlands should differentiate itself from other countries by offering a high level

of infrastructure and services, with Switzerland as an example

A. Huisman, MSc (PRA International)

65


7 September 2010, Zuidlaren

Name: Arnoud Huisman, MSc

Organization: PRA International

Title: Vice President Clinic

Description of the Organization: PRA International (PRA) carries out world-wide clinical

research on the efficacy of medicines in humans for pharmaceutical and biotech companies. In

the Netherlands PRA (formerly Pharma Bio-Research) has 450 employees divided over four

locations in the Northern part of the country PRA performs clinical and bioanalytical research,

from first-in-man until proof-of-concept studies. In Nieuwegein PRA also has a small unit for

project registration (phase II and III) studies.

Professional background and role in organization: Arnoud Huisman has worked as Director

Marketing & Sales at Wyeth Pharmaceuticals from 1998 to 2004, and has worked as Vice

President Clinic at PRA International in Zuidlaren since 2004. He has been board member of

the ACRON since March 2008.


In the Netherlands, the regulatory timelines for Phase I trials are very favourable: it usually

takes only 2 weeks to obtain approval. This is particularly swift when compared to Germany,

where it takes 60 days or France, where it takes 3 weeks. In the US it takes 3 months to open an

IND (Investigational New Drug). For early phase trials, which are not usually long term trials,

this makes a considerable difference to the total duration. The fast approval process is due to

the fact that, the decision making power remains with the local METC and the CCMO is only

involved administratively. The CCMO has to follow the timelines of the local METC, and the

maximum time allowed by law is 60 days. This competitive position is threatened by

discussions concerning the arranging the METC approvals at a European level: a mutual

recognition system might lead to equal timelines for the EU and therefore no more advantage

for the Netherlands.


The competitive position of the Netherlands with respect to the brief time period required for

obtaining METC approval is a direct result of the implementation of the EU CTD (also see

above). It has taken some effort to convince sponsors that, the implementation of the EU CTD

did not have big impact on the Netherlands. The CA process is little more complicated than


66

before, and sponsors are nervous that, under the relevant implemented laws they will have to

submit the Investigational Drug Brochure (containing confidential information) to a local

METC without any control on confidentiality of individual members. For that reason sponsors

sometimes go to Switzerland, since the EU CTD is not implemented there.


Despite the high costs (see below), sponsors are interested in performing clinical research in

the Netherlands, due to the excellent scientific level of clinical research evident within the

country (e.g. more experienced than in the US): Dutch professionals can assist with protocol

designs and can apply their extensive experience.

Costs

The costs for a Phase I study are high compared to the other EU countries and the US. PRA is

relatively expensive for a sponsor: healthy volunteers come from all over the country and

travel reimbursements are therefore relatively high. Labour costs in the Netherlands are also

relatively high.


PRA recruits healthy volunteers to test the safety of a compound and to test patient efficacy.

Patient recruitment is a difficult task in the Netherlands. PRA is dependent on specialist

referrals. These specialists often wish to keep such patients for the industry sponsored (phase

II-III) clinical trials that they are participating in. PRA does not collaborate with first line of

care for patient recruitment.

PRA has its own recruitment agency and recruits between 2000 and 3000 subjects per year for

their clinical trials (about 10% consist of patients, the remaining part are healthy volunteers).

Recruitment of healthy volunteers is easier to achieve thanks to the use of advertisements and

the (good) volunteer participation reimbursement. For a sponsor, the access to patients is

more important than the costs. Patient recruitment is not hindered by a negative image of

clinical drug trials, but rather by a lack of awareness.


PRA currently does occasionally collaborate with hospitals. It is not possible to perform

oncology trials in the Phase I unit because, patients need to stay in the hospital environment

where they are treated. A potential option therefore, could be greater collaboration in order to

create a Phase I setting in the hospital and deliver the equipment and resources needed to

perform the trial. In the Netherlands, this creates all sorts of liability issues between the

parties, and therefore this is done by PRAs subsidiaries in Central Europe.


67

It would signal a marked improvement if specialists and hospitals were to show more interest

in Phase IIa Proof of Concept research: if this does not change, it is likely, that this type of

clinical research will move away from the Netherlands. It is remarkable that early stage

(ground-breaking) clinical trials do not appeal to investigators. Later phase studies are

apparently more interesting for the investigators.


PRA finds it hard to attract qualified staff, due to its location in the North of the Netherlands.

When the search for personnel is successful, employees tend to stay at the company for a long

time. A low turn-over rate is of course very favourable for the continuity and preservation of

knowledge for a company. With respect to recruiting qualified research nurses there is some

competition from the hospitals in Groningen.


Organizations like the ACRON and DCTF are gradually becoming more important in the clinical

research arena. They accomplished the feat of getting different parties in the clinical research

environment to the table for discussions. However, at this stage the improvements they have

made to the clinical research climate are not yet visible in daily practice when compared to

other countries. The CCMO recently initiated a discussion on the concept that all research data

should be published in the CCMO database, even before a study has begun. The CCMO

requested the opinion of Nefarma, but did not contact ACRON, although this idea would have

had a directly negative effect on Phase I research mainly conducted by Dutch CROs. This

indicates that the contact between ACRON and CCMO should improve as ACRON governs the

interests of the Dutch CROs. On the other hand, if the public health inspector has questions on

Phase I research, he does contact the ACRON which is a promising sign.

The conclusion reached here, is that there has been some visible progress, but the DCTF and

ACRON have to strengthen their position relative to the government, the CCMO and other

authorities.

The development of the mutual recognition of METC approvals in Europe may present a

putative threat for Phase I research in the Netherlands. Currently the Netherlands holds a

strong position because of the short timelines required for METC approval for phase 1 studies.

With the mutual recognition the durations to start a trial may get longer which could harm

Dutch CRO’s like PRA. Currently, PRA is the biggest employer in phase I clinical research in the

Netherlands and with regard to Phase I research they are a top-three player in Europe in

volume. For the purpose of keeping the strong position of PRA in the clinical research arena,

preventing the aforementioned harm, PRA must remain a strong organization with


68

international connections and authority. The CCMO could influence this decision, and it is

recommended that they collaborate with organizations such as DCTF and ACRON.

A further problem exists in that, within the Netherlands there are numerous different

organization working on their own individual problems and failing to join forces. Life Sciences

& Health could be an example of an organization that actually has been able to construct a

bridge between life science and health (biotech and development) and also should include the

CRO industry in their initiatives.


There will be an increase of insourcing knowledge by industry, especially with respect to Phase

I knowledge. This of course is an interesting development for PRA (and other Phase I units in

the Netherlands). Further, clinical research will be performed sooner on patients (rather than

additional studies in healthy volunteers).

The shift to early, pre-clinical studies due to new organ techniques is not to be expected:

eventually testing on humans is required to generate the desired data. Small steps will be made

(e.g. with cell-lines), however, it will always be through a surrogate and all the research needs

to go through the required phases anyway.


There has been a clear shift visible towards the emerging markets for Phase I research: 20

years ago 60% of Phase I research was conducted in Europe and 40% in the US. 5 years later

this had changed to 60% in US and 40% in Europe; the current figures sit at 30-35% in Europe,

40-45% in the US and 10-20% in Asia and LATAM. External cost savings will be levelled out by

the high number of internal costs required to manage the studies in these new countries.

Therefore, the reason for the shift can not only be attributed to cost efficiency, but mostly to

the fact that these countries provide much better access to patients.

The situation regarding Organon (MSD) is, in the short term very unfavourable. However, in a

year or two, these circumstances will result in an increase in outsourcing by the company

which will of course be beneficial to the CRO industry.


It would be helpful for the industry if the government appealed to the Dutch people to take

responsibility to collaborate and participate in improving health care, although it will be

difficult to convince people in the Netherlands (look at e.g. the donor codicil). The decision to

close-down the R&D unit of Organon (MSD) could not be prevented by the government, since it


69

is very difficult to interfere in the decision making of a multinational company. TI-Pharma has

been a very valuable government initiative. However, the lack of financial continuity makes it

impossible to build a proper knowledge based economy. An alternative could be to use

governmental funding in the start-up phase and to search for external sponsoring to ensure

continuity and independency.

SWOT Analysis

Strengths

For Phase I trials RA and METC approval

timelines are very good compared to

other countries

Excellent scientific level in clinical

research

Weaknesses

Limited long-term continuity of the

government to the knowledge economy

Opportunities

Strengthen the position of organizations

like the ACRON and DCTF towards the

government, the CCMO and other

authorities

The development that more Phase I

knowledge will be insourced

Threats

Mutual recognition system of METC

approvals at a European level

Lack of interest by specialist in

participating in early phase (phase IIa)

studies, this type of research will

disappear in the Netherlands

Shift to emerging markets for better

patient recruitment

Recommendations

Prevent the further centralization of the METC approval process in Europe in order to

keep our competitive position with respect to the timelines for performing Phase I trials

in the Netherlands

Improve the position of the Netherlands as clinical trial country by further

strengthening the position of organizations like ACRON, DCTF and Life Sciences &

Health

Ms. L. Becker (Quintiles)

70


8 September 2010, Hoofddorp

Name: Lisa Becker

Organization: Quintiles

Title: VP, Integrated Patient and Site Strategies and General Manager, Quintiles BV

Description of the Organization: Quintiles is the only fully integrated bio and pharmaceutical

services provider offering clinical, commercial, consulting and capital solutions worldwide.

The Quintiles network of more than 20,000 engaged professionals in 60 countries around the

globe works with an unwavering commitment to patients, safety and ethics. Quintiles helps bio

pharmaceutical companies navigate risk and seize opportunities in an environment where

change is constant. Quintiles BV works on international, multi-centre trials across many

therapeutic areas.

Professional background and role in organization:

Lisa Becker has been with Quintiles since 2007, and is currently Vice President, Global Head of

Integrated Patient & Site Strategies and General Manager of Quintiles BV. Lisa studied biology

and public health, and began her career in clinical research in 1984 as a physician assistant.

She relocated to Europe in 1989, and has since held several international positions, gaining

over 20 years of experience and expertise in biotechnology, pharmaceutical, medical devices,

and academic research and product development.


Since the implementation of the EU CTD in 2006, the METC approval process has become more

cumbersome and slow in the Netherlands. Before implementation, regulatory approval

generally took between 30 and 60 days, whereas now, approval timelines are substantially

longer. This makes the Netherlands less attractive as a location to sponsors of international

studies with precise recruitment timelines,

To achieve the goal of healthier humans by getting new and better medicines to patients, faster,

all stakeholders including policy makers, regulators, and sponsors should be working better

together. They should be made aware of the value of each of their contributions. With the

addition of stakeholder groups and multiple layers (i.e., local ethics committee), conflicting

interests have developed while there should be a common competitive interest.


71

Effects of EU CTD implementation

Since the implementation of the EU CTD, there has been a substantial and visible increase in

bureaucracy and the METC approval process has become very slow (see above). Neighbouring

countries such as Belgium are performing much better in that respect, because their approval

process is highly streamlined.

Negotiating site agreements

Site agreement negotiations need to be in place very quickly when starting up a clinical trial in

order to meet tight recruitment deadlines. Hospitals often have multiple layers of authority

(the Principal Investigator, the hospital board, the department, the laboratory, the pharmacy,

etc.) all of which can contribute to an inefficient and lengthy process. Sites with a solid

commitment to clinical research often perform better because they have established

infrastructure and streamlined processes. Sponsors should consider criteria such as this

alongside their normal feasibility assessments when choosing sites.


The Netherlands has traditionally been one of the best countries for medical care, due to the

number of expert clinicians, a focussed public health policy and practice, good access to care,

research/tech savvy population, and excellent networks for patient recruitment and specialist

centres. By extension, it was also considered a good clinical trial country. However, the quality

of clinical research is increasingly considered in the potential future market. And, despite the

excellent clinical care, not all investigators and their study staff are trained in and understand

the impact of Good Clinical Practice (GCP). In that sense, the Netherlands has some work to do,

and is comparatively less appealing.

The Netherlands has very good infrastructure in place for healthcare records. This facilitates

access to important population data for sponsors, which makes feasibility and patient

recruitment more streamlined. It also allows access and collection of valuable research

information (e.g. clinicalresearch.com, iGuard, Provenance).

The Netherlands is known for its numerous key opinion leaders, and often this is what attracts

a sponsor to a particular site. However, the participation of key opinion leaders is not always

beneficial to the conduct of a trial (see below).


One of the strengths of Quintiles is its rigorous site selection, based on historical quality and

recruitment data, systems and processes, and epidemiological data. One issue in the

Netherlands has been the lack of willingness by sites to adopt a more research-friendly


72

approach. Key opinion leaders are usually the motivation for a sponsor to bring a trial to the

Netherlands; however the sites in which they work may not have the quality systems and

processes to support the trial.

In order to keep the Netherlands an interesting and appealing country for the sponsor, it is

important for KOLs to be more demanding of (their) sites to ensure that are set up to support

clinical trials. Quintiles collaborates with the top-clinical hospitals (STZ hospitals) since they

are putting effort into process optimization and are delivering high number of patients and

good quality data.

One way to foster more involvement in a clinical trial by an investigator is to offer the

opportunity to pursue sub-studies. This will increase the value of the clinical research and

enable the investigator to gather data for a publication.

Quintiles works with a large network and database of 3.000 General Practitioners and it is not

difficult to recruit GPs, especially for a study with an interesting indication or new compound.

It is important however, to develop good working relationships with GPs and provide support

throughout the duration of the study, to ensure that they remain engaged and can manage the

increased demands of a clinical trial alongside their busy practices.


The training of Dutch clinical trial staff in ICH-GCP is good compared to other countries, and is

continuing to improve. CROs and pharmaceutical companies alike are training investigators

and research nurses in ICH-GCP guidelines. Furthermore, the implementation of the BROK-

course for academic hospitals has improved and ICH-GCP has been implemented in some

Master study curricula (e.g. Health Sciences at the VU).

The number one country in ICH-GCP education and compliance is the UK: they have many

different institutes and requirements to support this standard. To replicate this in the

Netherlands is perhaps not necessary and it could lead to additional hurdles or delays when

performing a trial. However, training of PIs and study staff, and creation of research

environment and infrastructure within the institution is key to continued success and further

growth.


Hospitals that have established infrastructure and experience in conducting clinical trials

produce better results. Key to this is having research desks in the hospitals, which become the


73

multidisciplinary platform for research, organization and administration of trials, streamlining

the process and improving productivity, and facilitating interface with PI and study staff.


Access to patients is extremely important to Quintiles and its biopharma customers and is a

key factor in determining where to conduct a study.

In general, a drop in patients per site has been visible in recent years in North America and

Western Europe, which has made sponsors more inclined to go to emerging markets where

patient recruitment is less challenging. Patient recruitment metrics are particularly low in the

Netherlands, perhaps because of its relatively small patient population, and competitive

research studies.

Quintiles drives patient recruitment through a focus on therapeutic areas and through

collaborating with sites in its prime and partner-site programme. This includes:

a.) A thorough review of investigators, before the study starts, to determine

recruitment expectations and plans including a review of specific patient pathways.

For phase IIIb chronic disease studies the Netherlands has performed drastically

better than other countries because of this approach

b.) Quintiles gives special attention to certain sites (prime sites) by providing support in

developing systems, processes and infrastructure that is conducive to clinical trials

c.) In addition, Quintiles has established collaborations with “partner sites”, which are

recruited because of their high standard of quality and commitment to clinical

research.

The infrastructure for patient recruitment for late phase trials is good. In diabetes,

hypertension and cardiology for instance, recruitment is brilliant due to the many patient

organizations, and collaborative physician organizations that facilitate patient recruitment.


There is a need for clearly defined roles in the clinical research industry and stakeholders

should respect each other’s work. However, they should at the same time cooperate

extensively and where possible create synergies. Quintiles works with Bio-tech companies in

venture capital collaborations: they assist them with research, and share the risks and the

profits.


74


The Netherlands has a very competitive market when it comes to finding talented, qualified

and trained clinical research (monitoring) staff. The high salaries, the good secondary labour

conditions and the competition make it difficult to attract and retain candidates. Economic

drivers have led to consolidation, and several smaller local CROs are merging with the global

CROs – resulting in a more full-service offering as opposed to single (monitoring) service.


Quintiles works closely with ACRON, DCTF, NVFG and other organizations. However the

industry as a whole in the Netherlands could do more to achieve a stronger position for the

country as a destination for clinical research.


Quintiles has noticed a shift to the East in the clinical trial activities (first to Eastern Europe

and now towards Asia), due to downward pressure on cost, good patient recruitment and

advances in quality standards in emerging markets.

Once the social and cultural challenges are overcome even more research will be conducted in

Asia and the Latin American countries. The quality in these countries will also improve. In

Eastern Europe start up is longer, but once a study is up and running, this is offset by fast

patient enrolment, a huge patient population, lower costs and equal quality. Further East, one

can benefit from a quick start up and lower costs, but the quality is not yet at acceptable

consistently comparable level.


The government could support the clinical research environment by establishing clear rules on

timelines and arrange for a less rigid interpretation of the EU CTD in order to promote the

Netherlands as a competitive country.

Is the Netherlands an attractive country to establish your company

The Netherlands can be seen as a good place to start-up or expand a company. It is a gateway

to Europe, has a relatively high number of university graduates and experienced professionals,

and the tax benefits/structure for non-EU countries can be very attractive. However, there is

also the perception that the Netherlands does not have a favourable environment in which to

establish/operationalize a company: it has the highest percentage of part-time workers (male

and female) in the world which some translate into the fear of less productivity, has a

comparatively low number of female executives, and has employment law that favour the


75

employee. On balance, the Netherlands is a good place to set up operations – for both

companies coming from established and emerging market countries.

SWOT Analysis

Strengths

Good infrastructure for Phase IV studies

Good standard of medical care

Favourable company tax regulations

Weaknesses

Relatively small patient population and

market size

Increased bureaucracy due to strict

interpretation EU CTD

Difficult site agreement negotiations

Increased ethics approval timelines

Opportunities

The Netherlands has infrastructure for

phase IV clinical trials, and can be rolled

out to broader population base (i.e.,

vaccine studies)

Threats

Lack of research-friendly KOL

mindset/site infrastructure

Increased costs

Industry trend moving research to the

East

Recommendations

The ACRON and other representative bodies should have a broader say (stronger lobby)

in the rules concerning the conduct of clinical research in The Netherlands.

The clinical trial infrastructure in the Netherlands (at multiple levels) should be

improved.

KOLs should facilitate closing the gap between excellent clinical care and excellent

clinical research.

There should be an increased focus on patient access themes: a high patient enrolment

and excellent site relationships are essential for attracting clinical research.

H.J. Out, MD PhD (MSD)

76


6 September 2010, Oss

Name: Henk-Jan Out, MD PhD

Organization: Merck, Sharp & Dohme (MSD)

Title: VP Clinical Research, Women's Health & Endocrine

Description of the Organization: MSD B.V. is the non-American subsidiary of Merck & Co, Inc.,

and has been a leading company involved with innovative medicine in the Netherlands for over

fifty years. In July of this year, following a thorough reorganization of their Dutch affiliate

Organon, it was announced that all R&D activities in the Netherlands are to be stopped. At the

beginning of September this decision was postponed until the end of the year, to further assess

alternative business development opportunities.

Professional background and role in organization: Henk Jan Out has been working for

Organon since 1992. Organon was acquired by Schering-Plough, and later by MSD. He started

as the Medical Research Project Manager (Infertility) of the Clinical Development Department

and is now working at MSD as VP Clinical Research, Women's Health & Endocrine. In addition,

he is a professor of Pharmaceutical Medicine at the Radboud University Nijmegen Medical

Centre.

Ethics committee (EC) approval process

For an international company, the METC approval process found in the Netherlands, is not the

most arduous process such a company could face. To give some examples: in China it takes a

year between protocol submission and study start. In Brazil it takes it also takes a significant

period of time before the trial can begin. Yet, these countries remain very popular for industry-

sponsored trials. The eagerness of the investigators to participate in clinical trials and fast

patient recruitment are more important factors than the METC approval process. Obviously, a

long period spent obtaining regulatory approval does not favour the Netherlands, because the

industry prefers countries where the regulatory process is less cumbersome.


The implementation of the EU CTD did not have an influence on the competitive position of the

Netherlands within Europe, since the effects of implementation do not widely differ from other

countries where the EU CTD is implemented.


77

Negotiation of site agreements

Site agreement negotiations are not an important issue in the Netherlands, despite the fact that

there is usually a little more discussion on the publication section than in other countries.

However, troublesome contract negotiations at an international level can certainly be a

delaying factor, especially now that hospitals have their own lawyers who amongst other

things are often keen on more favourable intellectual property language for their client.


The Netherlands is performing very well on the clinical research front: there are high

publishing figures, the country and its expertise are always well presented at the important

conferences and there are also many key opinion leaders. The Netherlands is also very visible

in clinical drug research with new compounds, and studies that need scientific input.

Costs

The Netherlands is not greatly expensive with respect to investigators payments when

compared with the US for example. Scientifically educated staff are relatively cheap in the

Netherlands.


Some investigators are not interested in industry sponsored confirmatory trials, due to the lack

of a possibility for scientific input or authorship of publications. In contrast, other investigators

can see the benefit of generating income from this type of study and use it for more interesting

research. For example, one Dutch professor was involved in several large phase III studies with

antithrombotics which generated enough income to set up two or three other types of research

and also allowed the Professor to negotiate several sub-studies with the sponsor. For an

investigator, a trial with a new compound is usually of interest. In general, Dutch investigators

are better equipped and motivated for clinical trials that require scientific input (usually early

phases), since they are more academically than operationally oriented.

For key opinion leaders it is easier to negotiate interesting terms for participation in a trial,

such as sub-studies and publication rights. Furthermore, it is commonly known that key

opinion leaders are good for PR (Public Relationships) purposes. However, such individuals are

usually not very good performers in a trial and therefore it is important for a pharmaceutical

company to find a balanced mixture of investigators that are able to deliver work of good

quantity and quality. Investigators in the Netherlands are often somewhat presumptuous

compared to investigators in e.g. the Asian countries, although the latter are also in the

possession of high quality education and technology. Trials involving general practitioners are


78

usually not performed by pharmaceutical industries, since this is logistically very difficult (e.g.

ensuring that all participating GPs are trained on ICH-GCP).


Education in the Netherlands is considered internationally to be of a very high standard.

Knowledge of ICH-GCP by investigators is also improving (e.g. introduction of BROK-course5).

The failure of the probiotics trial at UMCU6 revealed that universities in the Netherlands may

very well underestimate clinical trial regulations, and it has made investigators aware that

conducting trials is not a secondary task, but requires accuracy, commitment and preparation.


An important consideration for the industry, when performing a trial at an international level,

is to look for countries where patients are available. Although it is not the only factor that

influences the decision, countries in Asia, Eastern Europe and Latin America (LATAM) are,

(because of the availability of large amounts of treatment-naïve patients) from a recruitment

perspective, more appealing than the Netherlands.


There is a desire in the industry to collaborate more with universities in the mutual

understanding of each other’s objectives and interests.


In a global pharmaceutical company, the decision to make use of a specific CRO is made

internationally: for multi-country studies international CROs are always used and often there is

a preferred provider relationship with such a CRO. It is therefore not really worthwhile

attempting to put the Netherlands on the map as a good CRO country (for the later phase

trials). Only in countries where there is not yet a great deal of experience (e.g. in Asia) is it

especially important to collaborate with a high quality CRO that is excelling in the local market.


Nefarma currently plays an important role in the ongoing discussions in the Netherlands, and

maintains good communication and cooperation with the government. The DCTF still has to

strengthen its position more, but is heading into the right direction.

5 Basiscursus Regelgeving & Organisatie voor Klinisch Onderzoekers (BROK)

6 The PROPATRIA-trial, a clinical trial performed from 2003 to 2007 to assess whether a pro-biotic supplement

would decrease the chance of infection for patients with a “predicted severe acute pancreatic”


79


Henk Jan Out expects that, in the near future, the emphasis in the clinical research process will

shift slightly and focus on early clinical activities: pharmaceutical companies are eager to get

greater security at an early stage as regards the effectiveness of a compound, since failures in

the later phases of the drug development process are very costly. Translational medicine as

such will become even more important and the Netherlands has a very strong presence in this

area (CHDR, Leidse farmaceutische wetenschappen). Predicting pharmacodynamic effects is

cost efficient and the Netherlands enjoys success in this area as it requires greater academic

expertise (many of the Top Institute Pharma (TIPharma) projects are this type of trial).

The later phase confirmatory studies do not usually require much scientific input, and as such

the Netherlands is not a very interesting country: “production work” will shift to low cost

countries. Gradually our strengths (knowledge, techniques) become available in other

countries that are eager for knowledge, are less expensive, can provide large amounts of

treatment-naive patients and in addition provide the opportunity to grow and have a large

potential market. However, the cultural differences remain a significant hurdle when

performing clinical research in the emerging markets.

Pharmaceutical companies are looking for a good “geo-mixture” of countries in which to do

their trials. They will expect an environment which delivers good quality data and at the same

time increases the chance for market access. Since the Netherlands is only a small country, and

the pharmaceutical industry conducts its business globally, it is important to focus on

international collaboration and not to build in additional hurdles that make us less attractive

than other countries (stricter regulations, slow approval process etc.).

The international development that negative findings need to be published as well as the

positive findings and that transparency is encouraged, is an improvement but could also be

used for less constructive purposes.


MSD announced on the 8th of July this year that it planned to close the R&D unit in the

Netherlands, a decision which has now been postponed until the end of the year. This could

mean that interesting job opportunities in the industry within the Netherlands will cease to

exist. The closure of the R&D unit in Oss could consequently result in a translocation of

promising investigators that are educated in the Netherlands to very complex research topics

abroad. Thus the knowledge that we have in the Netherlands would be used in countries

abroad. It is obviously undesirable, if there is investment in the education of Dutch

investigators and the Netherlands cannot benefit from the knowledge gained.


80


If the government wants a knowledge based economy, they will have to invest and make their

objectives and plans visible. The establishment of TIPharma is an excellent initiative, and

facilitates solid scientific research by a large number of investigators. The problem here is, that

the funding for TIPharma is assigned for three years, and now that the government is under

resignation (MRT: at the time of the interview there was no new government yet) a bridging

advance of 6 million Euro is assigned, and the new government has to decide again how to

proceed with the institute. However, if you want to use TIPharma to build your knowledge

economy, you should show a long term vision and approach.

In other ways, the knowledge economy has not yet gotten started, because there is no

willingness to invest, unlike in Finland for example, where investment has established Finland

as a leading country in drug innovation. The government should link economic activities with

scientific and healthcare activities. An example here is the example of MSD making a huge

investment in the Netherlands by establishing a production unit for vaccines in Haarlem, which

created approximately 200 jobs and the government subsequently decided to use the vaccine

of a competitor in the vaccination program. Adequate collaboration between all stakeholders in

the Dutch political system is therefore required. It will be attractive for a pharmaceutical

company to invest in the knowledge economy and to provide employment in the Netherlands,

if it knows that their medicines (after regulatory approval) will also be reimbursed.

Is the Netherlands an attractive country to establish your company

The government should link economic activities with scientific and healthcare activities (see

above), make investments to boost the knowledge economy and establish favourable measures

to make the Netherlands a more attractive country to settle for the industry. Company taxes

are very attractive. However, local strict labour regulations may make it less appealing for

foreign companies to invest and settle in the Netherlands.

The image of the industry is not positive and there is a wrong perception of how the industry

performs its trials. Some powerful individuals constantly present their negative opinion on the

industry in the media and seem to forget the positive contribution the industry has on health

care (e.g. AIDS is now a chronic instead of a lethal disease due to innovative anti-HIV drugs)).

Furthermore, in the Netherlands it is difficult to get a compound on the list of medicines that

are reimbursed by insurance companies. An additional hurdle for pharmaceutical companies is

that general practitioners are reluctant to prescribe new compounds, since they are only just

on the market, and long-term safety data is not yet available. This attitude of many Dutch GP’s

is working against innovation and is discouraging and damaging for the industry.


81

SWOT Analysis

Strengths

Many publications

Many investigators with special

expertise/Key Opinion Leaders

Not particularly expensive if compared to

other countries

High quality of education

Favourable company tax system (is

appealing for a company if establishing an

office)

Weaknesses

Not a large patient population available

Not a strong “production” country

No long term vision from government on

knowledge economy

Lack of collaboration at government level

to link economic and scientific and

healthcare activities

Rigid labour law (scares away potential

local subsidiaries)

Image of the industry is not good, due to

politics, media and some individuals

from the academic world

GPs reluctant to prescribe innovative

(registered) medicines

Opportunities

The shift to early stage translational

medicine: the Netherlands is good at this

type of studies

Better political collaboration to make the

Netherlands an appealing country for the

industry to invest in

Further improve ICH-GCP compliance

Collaboration between industry and

academic hospitals

Threats

A slow METC approval process will make

the industry choose countries that are

faster

Shift to less expensive countries with

large patient populations

The drug market is growing in the

emerging economies

Departure of promising scientists to

other countries where they have better

opportunities


82

Recommendations

Improve international collaboration in order to keep a participating position as a

smaller country in the clinical research environment

Improve political collaboration EZ, so that a link can be made between economic

activities with scientific and healthcare activities and the government can create

exciting and appealing opportunities for the industry (and consequently for the Dutch

research environment)

Further improve ICH-GCP compliance and awareness of investigators

Take advantage of the trend that emphasis will shift to the earlier phases in clinical

research for cost efficiency reasons, and sell our expertise on translational medicine,

predicting pharmacodynamic effects and other early phase research, because this is one

of the Netherlands’ biggest strengths

Stimulate further collaboration between industry and academic hospitals

The government should create a long term vision for establishing and stimulating our

knowledge economy

A. Keijzer, MSc and A.G.M. van de Langerijt, MSc (Sanofi-aventis)

83


8 September 2010, Gouda

Organization: Sanofi-aventis Netherlands B.V.

Description of the Organization: Sanofi-aventis focuses on development, registration,

marketing, sales and distribution of prescribed medicines. Sanofi-aventis is the third largest

pharmaceutical company in the Netherlands and has approximately 200 employees. Sanofi-

aventis is a member of Nefarma and in early 2009 joined as a partner in the Mondriaan project

from the Top Institute Pharma (TI Pharma) foundation. In the Netherlands, Sanofi-aventis

performs mostly phase II to IV studies, as part of multi-country studies, but also local phase IV

studies. The clinical research department of Sanofi-aventis consists of 45 people working solely

on clinical research.

Name: Angelique Keijzer, MSc

Title: Clinical Support Manager

Professional background and role in organization: Angelique Keijzer has been working at

sanofi-aventis (formerly sanofi-synthelabo) since 1997: first as Clinical Research Associate,

then as Clinical Project Manager and since January 2005 as Clinical Support Manager. She is an

expert on EUCTD and local legislation, METC approvals, SOPs and training within the

department.

Name: Lex van de Langerijt, MSc

Title: Director medical affairs & Clinical operations

Professional background and role in organization: Lex van de Langerijt has been working at

Sanofi-aventis since 1994 and is currently Director of Medical Affairs & Clinical Operations and

is also head of the Clinical Research Department in the Netherlands.


The CA approval process in the Netherlands is very fast compared to other EU countries (we

only have a marginal assessment). The approval process of the METC is on the contrary a

hurdle to performing clinical research in the Netherlands. In the experience of Sanofi-aventis,

the Netherlands is performing fairly well with respect to the time period between submission

and the first patient entering the study. However, before METC approval is obtained for all

sites, the Netherlands is often the last in the que and also frequently comes after the US. There

is a visible trend by which METCs and local feasibility committees implement adjusted

procedures that are more efficient (smaller committees, separate committees etc.). There is an

awareness that they have to be efficient in order to deal with the workload and also to be

competitive.


84

An article (supported by Sanofi-aventis7), concerning the vision of local feasibility committees

on the local feasibility assessment, has made clear that in their view the problem is not the

committee, but instead, the long time taken by the investigator in preparatory work. Sanofi-

aventis’ suggested solution is to assist the investigator with this preparatory work and to

remain on top of the progress of the collection and preparation of the required documents and

procedures. This has been shown to be very effective, but only because Sanofi-aventis has been

willing to provide the necessary resources.


Initially, the implementation of EU CTD did not really signal an improvement with respect to

the METC approval process, due to the fact that local committees did not trust each other’s

assessment, and consequently an approval for all sites was required anyway (although the idea

was to centralize the process and be more efficient). Gradually this situation is improving (see

above). The implementation of the EU CTD has resulted in a higher administrative burdens,

brought about by the extensive reporting regulations etc. In order to build expertise and

consequently be more time efficient Sanofi-aventis established a start-up unit that is focused

on submissions and other important start-up activities. Harmonization throughout Europe is

not really visible when performing an international trial, since all countries have implemented

the directive in a different way (only the minimum requirements are identical). In order to

comply with all local requirements, Sanofi-aventis has to bother the investigators with more

administration and reporting than is strictly necessary. However, this situation does not have

an effect on the competitive position of the Netherlands.

The factors that do have a negative impact on the competitive position of the Netherlands are:

the slow local feasibility committees, the more stringent requirements for trials concerning

orphan diseases, paediatric trials and gene therapy studies. The approval process at the Central

Committee on Research Involving Human Subjects (CCMO) for gene therapy studies is

troublesome and in addition there is a legal obligation requiring the presence of safety officers

in the hospital. An example of this troublesome process occurred during a study initiated by

Sanofi-aventis. Whereas all other countries involved did not classify the product studied as a

genetically modified organism, the Netherlands did and as such it was subject to CCMO

approval. This approval process lasted a year and with the trial eventually being rejected.

Sanofi-aventis visited the CCMO to clarify the failures in the process and established that there

was not enough progress surveillance and also that the management infrastructure was not of

7 Martine van Duijn, student BioPharmaceutical Sciences Universiteit Leiden and trainee at sanofi-aventis the

Netherlands BV: Edit leijendekker, Country Research Manager, Astellas Pharma BV (Draft)version 15 June 2010 –

“Toetsing van de lokale uitvoerbaarheid; de visie van toetsingscommissies”


85

a sufficiently professional level (e.g. the CCMO was not reachable for a period of 3 months

during the above process). Sanofi-aventis is confident that the CCMO will not let this happen

again. However, the requirement for assigning safety officers in the hospital is not very

attractive from a cost perspective, especially if actual patient recruitment is not certain.

When obtaining a request from the head office, Lex van de Langerijt now rejects this type of

study immediately. This development is of course a threat to this type of research occurring in

the Netherlands, and it is pre-eminently an area of research where the Dutch can play an

important role. Because of the very technical and scientific level of this kind of research, there

is high interest in performing these trials in the Netherlands. This is confirmed by the fact that,

when Lex van de Langerijt rejects this type of study, the head office of Sanofi-aventis will

attempt to find alternative circumstances in which to perform the trial in the Netherlands

(although for other studies it is very difficult to get on the list in the Netherlands).


METCs are indicating that they will benefit from standardized patient informed consent forms

and clinical trial agreements and Nefarma is working on both. The CCMO has initiated a

standard clinical trial agreement based on the UK NHS Trust Hospitals template and Nefarma is

now fine-tuning the template with the involvement of parties like the NFU, STZ, NVZ, NVMETC,

ACRON and the CCMO. The requirement from the CCMO that signed agreement must be

submitted before approval causes delays and other issues: sometimes the budget is not even

approved by the head office of Sanofi-aventis at the time of submission.


The Netherlands is known for its qualified investigators and the technical experience and

knowledge required to perform the most complicated clinical trials. In addition there are some

very good research networks that facilitate patient recruitment for certain therapeutic areas

(see below).

Costs

Cost efficiency has become more important when selecting a country in which to conduct the

clinical trial, since nowadays the execution of the more straightforward studies can also be

done in other (less costly) countries: the quality in countries like India and in Eastern Europe is

also very good.


The recruitment and motivation of investigators depends mainly upon the therapeutic area or

the product. It is easier to recruit investigators for a new first in class product than for a


86

product that is the fourth in row. If the drug is not very interesting, the investigator will only be

attracted if the investigator fee is substantial, but even then motivated investigators are hard to

find.


The problem in the Netherlands, is that there is no central registration of ICH-GCP trained

investigators. To date only BROK-course participants are registered. Furthermore,

pharmaceutical companies do not accept each other’s ICH-GCP courses which is very

inefficient. Seemingly, there is a lack of trust in the quality of the other party. Most

pharmaceutical companies will accept a registration, if the investigator did the ICH-GCP

training at the company concerned or from an accredited institute (like the BROK-course).

However, it is difficult to define an accredited institute and efforts to set up a central institution

for exams and registration acknowledged as such by all stakeholders (e.g. by Mediavision and

the Foundation “Certificering Klinisch Wetenschappelijk Onderzoeker” (see www.ckwo.org))

were not successful.

The most efficient method would involve all investigators being obliged to receive ICH-GCP

training at an accredited institute. The successful participants would be registered centrally

and follow a refresh-course every few years. This would also solve the issue that the Principal

Investigator is usually not interested in doing the course and sends the research teams to the

investigator meetings (where ICH-GCP training is provided). This is not difficult to arrange and

would contribute enormously to the improvement of the clinical research climate in the

Netherlands. It would also be helpful if the course was part of the training curriculum for

investigators or medical schools.


Research desks are very helpful in supporting clinical trial activities within hospitals. However,

they often function per department and are mainly focused on contractual activities instead of

the communication between the laboratory and the pharmacy. The laboratory and the

pharmacy often wish to have a separate agreement with the sponsor, because of budget

reasons. It would be advisable if a hospital would set-up a pool of nurses that could be used

throughout the departments in an efficient manner and facilitate good quality collaboration

with the pharmacy and the laboratory.

Sanofi-aventis is working on an initiative called Research Proof. This initiative has been set-up

to support hospitals in identifying bottlenecks when performing a clinical trial and to obtain

good insight into: their research management, to create harmonization and lastly to create the

opportunity to learn from other hospitals. The results of the assessment can then be discussed


87

with the hospital board. In this way an effective measure scan can be taken to improve the

clinical research process in hospitals.


The clinical trial industry is usually portrayed in the media and by the government in a very

negative way. This perception also influences the decision by patient to participate in a study

and consequently might lead to discouragement of the investigators (because of slow patient

recruitment). Nefarma is trying to improve the image of the industry by way of informative

leaflets etc.

The relationship with their treating physician is however usually the most decisive factor in a

patients decision to participate. Therefore, these relationships are crucial for the success of a

clinical trial. It also helps that the Netherlands has an excellent infrastructure and good

networks like the WCN and VCRN (cardiovascular network). The local Sanofi-aventis research

unit can bring large cardiovascular studies to the Netherlands due to this type of network.

Access to patients is more important to a pharmaceutical company than costs.

However, Diabetes research has become more complicated in the Netherlands owing largely to

a shift to the first line of care, and the lack of interest among general practitioners to

participate in a clinical trial. This makes it more difficult to get diabetes trials to the

Netherlands, since in other countries the diabetes patients remain with the specialists. Sanofi-

aventis has invested for years in the motivation of the care groups and GPs, which has proven

to be a difficult task. Another down-side is that the patients are spread in small amounts over

the GP practices and therefore recruitment is slower. GPs are also often not sufficiently

equipped to participate in clinical trials.

Sanofi-aventis uses a very strict and thorough selection procedure to ensure that a site is

motivated, well prepared and able to recruit the estimated number of patients. If a study is

initiated by the head office, the local Sanofi-aventis office has to work through an extensive

feasibility questionnaire to, amongst other things, assess the recruitment potential, with only a

5% chance that the Netherlands is selected.


Sanofi-aventis conducts most of its clinical research internally. Only where big international

studies are involved, for which the resources are not in house, will CROs get involved. This

decision is made at a corporate level and the CRO contracted is always an international one.

Sanofi-aventis has had good and bad experiences with CROs. Sometimes the conduct of a

clinical trial is also difficult for the CRO, due to restrictions initiated by the client.


88


The current trends in clinical research are:

1. trials with small indications, development of specific innovative drugs

2. personalized medicine, medicine developed for genetic subsets

3. antibiotics research (because of the resistance that is developed for existing antibiotics)

4. ageing diseases

5. paediatric trials

Following the introduction of the Medicines for Children Research Network (MCRN), 2 years

ago, the Netherlands has the potential to take a leading position. The MCRN unfortunately has

not yet received enough projects, and is bound by the stringent regulations found the

Netherlands (compared to other EU countries). For example, when parents of children with

Duchenne collected money for research, the research could not be performed in the

Netherlands because of stringent regulation. Therefore it was decided to conduct the trial in

other EU countries. In the opinion of Angelique Keijzer and Lex van de Langerijt, paediatric

trials are the future and it is a real opportunity for the Dutch clinical research arena to excel in

this type of trial.


Due to the low costs and also the large number of available naïve patients, industry is shifting

to the emerging markets. Asthma and diabetes studies are not performed in the Netherlands by

Sanofi-aventis due to the difficulty in finding and recruiting naïve patients. Russia has a long

start-up period, but this is now standard because of their fast patient recruitment. Europe will

never be completely ignored, because companies will often want to submit to the EMA which

requires different genetic populations. The danger remains that due to cost efficiencies the

sponsors will choose bigger countries in Europe that can deliver more patients (e.g. UK, France

and Germany). Due to its size, the difficulty faced in getting the compound on the

reimbursement list and the reluctance to prescribe new medicine, the Netherlands is not seen

as very appealing in future market potential.


It is a troubling development, that R&D units of large pharmaceutical companies are leaving

the Netherlands. In the case of Organon (MSD) the Dutch government has chosen to apply the

free market principle, although it seems that Sarkozy was able to save the MSD units in France

by communicating directly with the CEO of MSD. This attitude is not in line with the innovation

platform and the desire for a knowledge based economy. The government also fails to show

enough long term vision in this area (see TIPharma).


89

SWOT Analysis

Strengths

Qualified investigators and study teams

Well-equipped to handle more technical studies

Weaknesses

Slow local feasibility process and

therefore slow METC approval

process

Inefficient ICH-GCP recognition

infrastructure and lack of a

mandatory training and central

register

Lack of a good and central

research structure in hospitals

Opportunities

Adjust the requirements for orphan disease,

paediatrics and gene therapy trial to the

requirements in other countries in the EU (now

our laws are more stringent), so that the Dutch

clinical research environment can benefit from

the fact that this type of studies is pre-eminently

interesting for their more unique technical

knowledge and experience

Further strengthen MCRN network and draw

international attention in order to increase the

number of projects so that we can build

experience

Arrange for centralized registration and the

obligation to follow ICH-GCP training at an

accredited institute. Assign a few of these

institutes.

Create initiatives that can improve the clinical

research structure at the hospital and create

awareness with the hospital boards

Threats

Stringent regulations for gene

therapy and paediatric studies are

a missed opportunity for the

Dutch technical research

environment


90

Recommendations

Adjust the requirements for orphan disease, paediatrics and gene therapy trials to

mirror those requirements in other EU countries (now our laws are more stringent), so

that the Dutch clinical research environment can benefit from the fact that this type of

studies is pre-eminently interesting for it’s more unique technical knowledge and

experience

Further strengthen the MCRN network and draw international attention in order to

increase the number of projects so that we can build experience

Arrange for centralized registration and the obligation to follow ICH-GCP training at an

accredited institute. Assign this to several institutes.

Create initiatives that can improve the clinical research structure at hospitals and create


Streamline the mind-set of METCs, industry, investigators, hospital boards, patients and

government to build a stronger research climate in the Netherlands

91

J. Rijnierse, MD (Amgen)

23 September 2010, Breda

Name: Joep Rijnierse, MD

Organization: Amgen BV

Title: Medical Director

Description of the Organization: Amgen BV is a Biotech company focused on clinical

research, marketing and sales. Their special indication areas are oncology, kidney disease and

rheumatoid arthritis. Amgen BV is participating in international multi-centre phase II to IV

trials.

Professional background and role in organization: Joep Rijnierse has been working in the

clinical trial industry for 23 years. He has worked in a number of different roles, including:

Medical Advisor, at Ciba-Geigy, was International Clinical Research Operations Manager at

Novartis, Medical Director at Pharmacia (& Upjohn) (later acquired by Pfizer), Manager

Corporate Affairs at Pfizer, Global Medical Director Neurology at Serono, Medical Director the

Netherlands at Schering-Plough and since August 2009 he works as Medical Director at Amgen

BV. For the last 3 years, Joep Rijnierse has been actively involved in a working group from

Nefarma aiming to improve the Research and Development climate in the Netherlands, and for

which he elaborated on the laws and regulations in the Netherlands and the infrastructure in

the hospitals. The vision with some recommendations and standpoints from Nefarma will be

made public in the near future.


The METC approval process in the Netherlands is slow. Academic centres attempt to

undermine each other and do not trust each other’s assessments and opinions, resulting in

substantial delays to the approval process. A “Locale Uitvoerbaarheids Toetsing (LUT)” is very

often done by a METC which does not restrict itself to doing the LUT, but again performs an

ethical review. In the case of competitive recruitment, delays to the approval process result in

a situation where the Dutch sites are opened when all patients have already been included in

the trial process and other countries have already finished their trial. The METCs of

universities should take a united stance as some academic centre already did and not redo an

ethical approval. If the Netherlands would like to remain competitive with other countries

then it must be acknowledged that it is too small a country to have different opinions in eight

different centres. Discussion and debate on smaller issues must of course be allowed, but this

should be kept out of the approval process.

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Delays affecting the trial process are not caused by a lack of rules and regulations or a failure

to collaborate between investigators, but by the separate assessments of the local feasibility

committees. The difficulty here is that the only entity authorized to correct and instruct the

committees is the hospital board, and clinical research is usually not on its agenda. The CCMO

and the Dutch Society of Ethics Committees (NVMETC) do not possess the authorization and

the tools to correct and exert pressure on the committee. Positive exception are the METC and

local feasibility committee in the Erasmus MC in Rotterdam and the Leiden University Medical

Centre: they have constructed a very efficient process and understand that this makes them

competitive. The infrastructure of a hospital is in this perspective extremely important,

because it creates the basis for clinical research in the hospital and provides a voice to the

hospital board.


The implementation of the EU CTD brought with it additional administrative burdens.

However the other EU countries are dealing with those issues as well, and as such it does not

have an effect on the Netherlands’ competitive position, except for implementation of the

CA/METC review. Bureaucracy in the Netherlands remains less than that in the US, but diligent

monitoring will be required in order to maintain the status quo and continue to enjoy this more

favourable position.


Nefarma is working on the standardization of patient information and the clinical trial

agreement. Nefarma is collaborating with the CCMO, hospitals and other parties on a standard

contract template and is now consulting different parties (such as the ACRON, NFU, NVZ) to

produce a document with a solid basis. All players in clinical research are content with the

development of a standard template. At the moment site agreement negotiations can be very

time consuming.


The infrastructure in place for clinical research and development in the Netherlands is in

principle very good. In some areas it has the status of an internationally leading player. In

order to remain competitive, further improvements in those areas is required. Additionally,

the Netherlands should be very selective in exploring and developing new areas of expertise. A

threat exists that other countries are developing too and in the meantime are often also in

possession of high quality equipment and facilities. The Netherlands continues to house many

Global Key Opinion Leaders (GKOL), and it is important to keep them in the country and give

them the means to continue to be involved in R&D: at the moment research and development

is moving away from the Netherlands, this will result in less publications and a down-wards

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spiral may follow. Currently, the Netherlands remains competitive in phase II early stage

research, complex research and Phase I research (also in oncology) and in selective later phase

research areas (e.g. cardiology, pulmonology, etc.) often done with Coop-groups.

Costs

The Netherlands is an expensive country when compared to other countries in Europe. In the

experience of Joep Rijnierse costs in the Netherlands are increasing. In addition to the very

generous investigator fee that is paid by pharmaceutical companies, hospitals often wish to be

reimbursed for overhead costs (sometimes as high as 16%) where one can wonder what this

is for since the procedures, METC, pharmacy, investigators, etc. are already paid for in full

(including overhead fee). The Netherlands does not have an interesting and appealing market

potential and if also more expensive than other countries, it will prove extremely difficult to

attract research and development to the Netherlands. The environment in the Netherlands

cannot and should not be compared to countries such as India or China with very low costs,

but it is important to remain competitive to comparable Western-European countries.


The Netherlands is particularly research-minded and hospital staff are aware that clinical

research improves patient health care and also quality of regular care. Investigators are

interested in studies where they can provide input into the protocol and have an opportunity

to publish. It is more difficult to motivate investigators to participate in late phase

international studies. Generating studies with general practitioners has become more difficult.

Reasons for this decline include feminization (more part-time GPs), the lack traditionally of

participation in clinical research and also the high workload of GPs. Some level of cooperation

has established good infrastructure for research, and these initiatives can be supported by

industry. Also cooperative groups in other areas have proven to work well and attracted

research to The Netherlands.


The hospital staff are usually well-trained. If the research is performed by medical doctors in

training or when staff frequently changes, it is difficult to provide the same level of training in

a hospital as if it was dedicated research staff. A good infrastructure in the hospital facilitates

ICH-GCP training. Some investigators have been careless regarding ICH-GCP training

requirement, but the industry has also been extreme in their un-willingness to acknowledge

training certificates from other sponsors. It would be beneficial to have certified training in the

Netherlands, so that besides a company’s own training regime, the certified training would

also be accepted. The BROK-course is a good initiative but very detailed and bureaucratic,

which is appropriate for the academies, but for the other hospitals it would be advantageous

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to also create a more practical version. Electronic training and exams can be very effective and

efficient. This should also be the solution to the problem that, investigators often do not attend

the investigator meeting (where an ICH-GCP training is provided) themselves.


Research desks at hospitals can be useful if they facilitate and support the investigator with

respect to resources and knowledge, and the department pays for the services used. A

situation where it is mandatory to perform all research in the hospital through a central

research desk would not work well: it will become bureaucratic, investigators will not be

happy with the fact that they cannot negotiate directly with the sponsor and the sponsors will

not be happy with the overhead costs associated with such a trial desk. There is a big

difference in the infrastructure for clinical research between different departments. A

considerable number of investigators are for example performing investigator initiated trials

with the infrastructure and income generated from industry sponsored research (e.g. most

academic centres and some STZ hospitals like Kennemerland).


In general patients are still willing to participate in clinical trials. Specialist are usually better

equipped to explain to the patient why they should participate than general practitioners. Also

they have often a bigger patient pool with a specific profile needed for a specific trial than GPs

do and therefore their recruitment rates are usually higher.


The industry is very interested in collaboration with academic hospitals. It does however

prove difficult to generate support from the head office of a pharmaceutical company for

participation in TI-Pharma projects because of the intent that TI-Pharma projects should be

projects before competition. For some interactions with academia intellectual property

arrangements can be very important for the industry and cause some discussions.


The initiative of the Medicines for Children Research Network (MCRN) which profiles the

Netherlands as a country for paediatric research is very inspiring, but not yet very successful.

The problem with this initiative lies in the fact that the network is current, but has not enough

yet garnered enough experience with regard to paediatric research. Sponsors are therefore

relatively cautious when it comes to conducting such a trial in the Netherlands (leading again

to no experience being built). The stringent regulations for this type of study are not helping

either.

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The closure of the Research unit from Organon (MSD) is not surprising when looking at the

management of large international company. When activities of one of the research units

worldwide, like the former Organon Research within MSD, are not fitting the research

direction a company wants to go or are, compared to other units, maybe not top-of the bill or

creating cutting-edge technology, a logical decision for such a company is to close down such a

unit, when costs have to be cut. The impact on the clinical research environment in the

Netherlands however, is underestimated: it is not simply the loss of jobs; but also the loss of

existing relationships and joint ventures with the academies (e.g. TIPharma) and the missed

opportunity of obtaining knowledge from students and talented scientists that will move

abroad. The research activities of other pharmaceutical companies can still be saved for the

Netherlands (e.g. by way of stimulating start-ups). Clinical development is another story.

Although the Netherlands has already lost some of these activities to other countries and

regions they still are competitive. The challenge here is to remain competitive wherever

possible. Both Research and Development activities fit with the strategy of the Dutch

government to become “Nederland Kennisland” and thus should have full attention which is

not always the case.


Politicians are not being supportive of the industry in the media. There is limited consistent

and close collaboration between the departments of VWS and EZ.

Is the Netherlands an attractive good country to establish your company

It is very difficult to get a compound on the list of reimbursed compounds in the Netherlands

and the process takes far too long. The image of the industry is worse than anywhere else in

the World. If the government provided incentives to industry to stimulate research and

development in the Netherlands, it would create a more appealing environment for a company

to settle in (see for example, the situation in Switzerland).

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SWOT Analysis

Strengths

Excellent phase I setting

Good in early stage, complex trials

Good functioning Coop-groups in certain

areas

Good well respected GKOL network with

high international impact

High number of spin-off and start-up

companies

Weaknesses

Slow METC/LUT approval process

More stringent regulations than other

European countries for some study types

Costs are high compared to other EU

countries

No constant quality in all departments in

academia and research oriented hospitals

Opportunities

Stimulate performance of interesting

clinical trials by establishing a good

infrastructure (financial incentives)

Stimulate more collaboration between the

eight academic centres and also with the

top clinics

Improvement of cooperation with

industry as a trustworthy partner (stop

only emphasizing negative image)

Improve infrastructure for R&D in

academia and peripheral hospitals

More participation of the patient

organizations

Standardization of CTA and PIF to

improve approval times

Threats

More bureaucracy with too much

workload

Loss of Global Key Opinion Leaders and

less involvement in global R&D

Catch up of quality R&D activities by

other countries

More trials allocated to CEE and BRIC

countries

Loss of leading position with global

impact (Leading KOLs, high impact

publication, leading universities, etc.)

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Recommendations

Further improve the infrastructure for R&D in centres, but also in The Netherlands as a

whole

Turn around the slow METC/LUT approval process (e.g. Improve LUT, standard CTA

and PIF)

Ensure that rules and regulations do not obstruct clinical research and implement in

such a way that NL becomes competitive again

Ensure that global KOLs will not leave the country and stay closely engaged in global

R&D

Create awareness within hospital boards about the importance of R&D

Wherever possible create collaboratively in research networks within or across centres

(Trial groups, cooperative groups, specialized network groups, etc.)

Create collaboration where industry is seen as a trustworthy partner

Provide financial incentives or other stimulants to the industry in order to strengthen

the Dutch clinical trial environment

STAKEHOLDER OPINIONS ON THE POSITION OF THE … · DCTF Dutch Clinical Trial Foundation EC Ethics...

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